Binding of O-alkyl derivatives of serotonin at human 5-HT1Dβ receptors

Article abstract of DOI:10.1021/jm950498t

In humans, 5-HT1D serotonin receptors represent terminal autoreceptors, and there is some evidence that 5-HT1D ligands may be useful in the treatment of migraine. The most widely used 5-HT1D agonist is sumatriptan; however, this agent reportedly displays little selectivity for 5-HT1D versus 5-HT1A receptors. To identify novel serotonergic agents with enhanced 5-HT1D versus 5-HT1A selectivity, we attempted to take advantage of possible differences in the regions of bulk tolerance associated with the 5-position of the 5-HT binding sites for these two populations of receptors. Examination of a series of 5-(alkyloxy)tryptamine derivatives demonstrated that compounds with unbranched alkyl groups of up to eight carbon atoms bind with high affinity at human 5-HT1Dβ receptors (K(i) < 5 nM) but demonstrate less than 50-fold selectivity relative to 5-HT(1A) receptors. Alkyl groups longer than eight carbon atoms impart reduced affinity for 5-HT(1A) receptors whereas groups longer than nine carbon atoms lead to compounds with reduced affinity at 5- HT1Dβ receptors. 5-(Nonyloxy)tryptamine (10) represents a compound with optimal 5-HT1Dβ affinity (K(i) = 1 nM) and selectivity (>300-fold). Branching of the alkyl chain, to 5-[(7,7-dimethylheptyl)oxy]tryptamine (15), results in an agent with somewhat lower affinity (5-HT1Dβ K(i) = 2.3 nM) but with greater (i.e., 400-fold) 5-HT1D versus 5-HT1A selectivity. Replacement of the oxygen atom of 10 with a methylene group (i.e., 20), replacement of the O-proximate methylene with a carbonyl group (i.e., ester 26), or cyclization of the aminoethyl moiety to a carbazole (e.g., 34, 36) or β- carboline (i.e., 37), result in reduced affinity and/or selectivity. None of the compounds examined displayed significant selectivity for 5-HT1Dβ versus 5-HT1Dα sites; nevertheless, compounds 10 (recently shown to behave as a 5- HT1D agonist) and 15 represent the most 5-HT1D versus 5-HT1A selective agents reported to date.

Full text of DOI:10.1021/jm950498t

3
14
J . Med. Chem. 1996, 39, 314-322
Bin d in g of O-Alk yl Der iva tives of Ser oton in a t Hu m a n 5-HT1Dâ Recep tor s
,
†
†
†
†
†
‡
Richard A. Glennon,* Seoung-Soo Hong, Mikhail Bondarev, Ho Law, Malgorzata Dukat, Suman Rakhit,
‡
‡
‡
‡
§
§
Patricia Power, Ermei Fan, Diana Kinneau, Rajender Kamboj, Milt Teitler, Katharine Herrick-Davis, and
Carol Smith§
Department of Medicinal Chemistry, Medical College of Virginia, Virginia Commonwealth University,
Richmond, Virginia 23298-0540, Allelix Biopharmaceutical, Mississauga, Ontario L4V 1V7, Canada, and
Department of Pharmacology, Albany Medical College, Albany, New York 12208
X
Received J uly 7, 1995
In humans, 5-HT1D serotonin receptors represent terminal autoreceptors, and there is some
evidence that 5-HT1D ligands may be useful in the treatment of migraine. The most widely
used 5-HT1D agonist is sumatriptan; however, this agent reportedly displays little selectivity
for 5-HT1D versus 5-HT1A receptors. To identify novel serotonergic agents with enhanced
5
-HT1D versus 5-HT1A selectivity, we attempted to take advantage of possible differences in
the regions of bulk tolerance associated with the 5-position of the 5-HT binding sites for these
two populations of receptors. Examination of a series of 5-(alkyloxy)tryptamine derivatives
demonstrated that compounds with unbranched alkyl groups of up to eight carbon atoms bind
with high affinity at human 5-HT1Dâ receptors (K < 5 nM) but demonstrate less than 50-fold
i
selectivity relative to 5-HT1A receptors. Alkyl groups longer than eight carbon atoms impart
reduced affinity for 5-HT1A receptors whereas groups longer than nine carbon atoms lead to
compounds with reduced affinity at 5-HT1Dâ receptors. 5-(Nonyloxy)tryptamine (10) represents
a compound with optimal 5-HT1Dâ affinity (K
of the alkyl chain, to 5-[(7,7-dimethylheptyl)oxy]tryptamine (15), results in an agent with
somewhat lower affinity (5-HT1Dâ K ) 2.3 nM) but with greater (i.e., 400-fold) 5-HT1D versus
-HT1A selectivity. Replacement of the oxygen atom of 10 with a methylene group (i.e., 20),
i
) 1 nM) and selectivity (>300-fold). Branching
i
5
replacement of the O-proximate methylene with a carbonyl group (i.e., ester 26), or cyclization
of the aminoethyl moiety to a carbazole (e.g., 34, 36) or â-carboline (i.e., 37), result in reduced
affinity and/or selectivity. None of the compounds examined displayed significant selectivity
for 5-HT1Dâ versus 5-HT1DR sites; nevertheless, compounds 10 (recently shown to behave as
a 5-HT1D agonist) and 15 represent the most 5-HT1D versus 5-HT1A selective agents reported
to date.
Serotonin (5-HT, 1) receptors have been divided into
several major families on the basis of pharmacological
properties, sequence data, and second messenger
volved in similar actions. To date, few 5-HT1D agonists
have been identified. Although 5-carbamoyltryptamine
(2) has been used as a 5-HT1D agonist, it is a nonselec-
1
-3
6
coupling.
Receptor families having received the most
tive 5-HT1 agent. Sumatriptan (3), the most widely
attention are the 5-HT1 (adenylate cyclase coupled),
used 5-HT1D agonist, is a fairly selective agent which
was recently introduced for the treatment of migraine
headaches. Although there is some controversy regard-
ing its exact mechanism of action in this regard, 5-HT1D
5
-HT2 (phosphoinositol coupled), and 5-HT3 (ion chan-
1
-3
nel) receptors.
5-HT1 receptors have been further
divided into several subpopulations that include 5-HT1A,
-HT1B, and 5-HT1D receptors. (Due to greater simi-
5
7
receptors are thought to be involved. Sumatriptan,
larity to the 5-HT2 rather than 5-HT1 family, 5-HT1C
receptors were recently renamed 5-HT2C receptors.) Of
particular interest to the present investigation are the
though fairly selective for 5-HT1D versus most other
populations of 5-HT receptors, displays only 10-50-fold
selectivity for 5-HT1D versus 5-HT1A receptors. In
addition to the difficulty of sumatriptan to penetrate
the blood-brain barrier, its lack of selectivity for
5
-HT1D receptors. Rodents possess 5-HT1B receptors,
which appear to function primarily as autoreceptors. In
support of this concept, the synthesis of 5-HT1B recep-
tors at the level of serotonergic terminals has recently
been demonstrated.4 Most other mammal species in-
cluding humans possess 5-HT1D receptors in corre-
sponding anatomical regions of the brain; thus, these
5
-HT1D versus 5-HT1A receptors detracts from its
7
utility as a tool for 5-HT receptor research. Further-
more, certain of sumatriptan’s clinical side effects may
be related to its affinity for 5-HT1A receptors.7 This
prompted us to identify a novel agent that binds at
1
-3
receptors appear to represent species homologs.
5
-HT1D receptors with an affinity comparable to that
There is evidence that 5-HT1D receptors modulate
of sumatriptan, but with greater 5-HT1D versus 5-HT1A
selectivity.
vascular tone and inhibit neurotransmitter release by
acting as terminal autoreceptors.1
-3
Studies with ro-
While our work was in progress, Weinshank and co-
workers identified two populations of human 5-HT1D
dents suggest that 5-HT1B receptors may be involved
1
,5
in aggression, depression, and other central actions.
8
receptors: 5-HT1DR and 5-HT1Dâ receptors. 5-HT1Dâ
Thus, by analogy, 5-HT1D receptors may also be in-
receptors display >90% homology with, and appear to
be the human counterpart of, 5-HT1B receptors.
5-HT1DR and 5-HT1Dâ receptors display >90% homol-
ogy in their transmembrane domains, and no high-
†
Virginia Commonwealth University.
Allelix Biopharmaceutical.
Albany Medical College.
Abstract published in Advance ACS Abstracts, December 15, 1995.
‡
§
X
0
022-2623/96/1839-0314$12.00/0 © 1996 American Chemical Society

Binding of O-Alkyl Derivatives of Serotonin
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 315
Ta ble 1. Physicochemical Data for O-Alkyltryptamines
O
CH2CH2NH2
2 2 2
CH CH NH
HO
C
no. methoda % yield RSb
mp, °C
empirical formulac
H2N
6
7
8
9
0
11
12
3
4
5
6
A
A
A
A
B
B
A
B
B
B
B
27
31
22
26
29
95
29
70
64
62
82
ME 159-160 C13H18N2O‚C2H2O4
ME 145-147 C15H22N2O‚0.9C2H2O4
ME 192-194 C17H26N2O‚0.5C2H2O4
ME 136-139e C18H28N2O‚C2H2O4
N
H
N
H
d
f
1
2
1
A
196-198 C19H30N2O‚HCl
O
CH3
ME 194-196
20 32 2
C H N O‚HCl
CH2CH2N
ME 190-191 C21H34N2O‚0.5C2H2O4
ME 193-195h C19H30N2O‚HCl
CH3HNSCH2
O
CH3
1
1
1
1
f,g
ME 196-198 C21H34N2O‚HCl
N
H
f
ME 173-175 C20H32N2O‚HCl
ME 189-191h C20H30N2O‚HCl
a
Method of preparation, see the Experimental Section. b Recrys-
3
tallization solvents: A ) EtOAc, M ) MeOH, E ) anhydrous Et2O.
c
All compounds analyzed correctly for C, H, N within 0.4%, except
affinity agents have been shown to discriminate be-
tween the two subpopulations. Sumatriptan (3), for
example, binds at the two 5-HT1D receptors with
where noted. d Crystallized with 0.25 mol of H2O. HCl salt; see
e
f
g
the Experimental Section. Crystallized with 0.5 mol of H2O. H:
calcd, 9.65; found, 9.18. h Decomposed.
8
affinities (Ki values) of 3.4 and 7.7 nM, respectively.
The past few years have witnessed the development
Ch em istr y
of several newer 5-HT1D ligands including a series of
O-Alkyl derivatives 6-16 were prepared by either one
9
5
-oxadiazolyltryptamines, 3-amino-6-carbamoyl-1,2,3,4-
1
5
of two methods (Table 1). In method A, the terminal
amine of 5-(benzyloxy)tryptamine was protected with
an acetyl group, the benzyl group was removed by
hydrogenolysis, and the resultant phenolic hydroxyl
group was alkylated using the appropriate alkyl halide.
In the final step, the N-acetyl-O-alkyltryptamine was
deprotected under acidic conditions to afford the desired
products.
1
0
tetrahydrocarbazole, and several 5-[(3-nitropyrid-2-yl)-
1
1
amino]indoles; however, none of these agents displays
greater 5-HT1D versus 5-HT1A selectivity than suma-
triptan. Two structurally novel 5-HT1D antagonists
have also been reported: GR127935 and GR133867;
these compounds display 50-100-fold 5-HT1D versus
5
-HT1A selectivity.12 Nevertheless, there is still a need
for 5-HT1D-selective agonists with greater selectivity
than 3.
Our approach to developing a 5-HT1D versus 5-HT1A
selective agent was based on the following observa-
tions: (i) because 5-HT binds with high affinity at
Method B involved protection of the terminal amine
of 5-HT (1) with a t-BOC group, O-alkylation, and
subsequent deprotection using acid hydrolysis. Nearly
all of the alkyl halides were commercially available;
however, those necessary for the preparation of 13-16
were synthesized according to literature methods.1
Tryptamines 18 and 19 were obtained from 5-eth-
ylindole using the Speeter-Anthony tryptamine syn-
5
-HT1A and 5-HT1D receptors, those portions of the
respective receptors that bind 5-HT likely are similar,
ii) both 5-HT1A and 5-HT1D receptors possess a region
6-19
(
of bulk tolerance associated with the aromatic portion
of 5-HT, (iii) 5-HT1A receptors allow considerable bulk
on the terminal amine whereas 5-HT1D receptors favor
smaller amine substituents, preferably primary amines
2
0
thesis; the prerequisite 5-ethylindole was prepared by
J app-Klingeman cyclization of 4-ethylaniline. Like-
wise, the 5-alkyltryptamine 20 was prepared using the
Speeter-Anthony method, and the required 5-n-decyl-
indole was prepared from 5-n-decylaniline using the
(e.g., refs 13, 14). Given that there is only about 50%
sequence homology between the transmembrane por-
2
1
tions of 5-HT1A and 5-HT1D receptors,1-3 we reasoned
general indole synthesis of Sugasawa et al.
5
-Acetyltryptamine (21) was synthesized by a litera-
that the regions of bulk tolerance should not be identi-
cal. That is, it might be possible to incorporate at the
indole 5-position substituents of varying lengths that,
due to potential differences in distant helical environ-
ments, will differentially bind with higher affinity at
one population of receptors over the other. We recently
reported one such agent that binds at 5-HT1D versus
2
2
ture method, and the esters 22-25 were prepared by
acylation of bufotenine as we have previously de-
scribed.
2
3
Ester 26 was prepared in an analogous
manner. Modification of the terminal amine of 10 by
reductive alkylation afforded 27 (NaCNBH3/H2CO) and
8 [CH3(CH2)2COCl/LiAlH4]. In one instance, an at-
2
tempt was made to prepare 27 by an Eschweiler-Clarke
reaction; rather than obtaining the expected 27, cycliza-
tion occurred to give 37.
5
-HT1A receptors with higher affinity and selectivity
1
5
than sumatriptan: 5-(nonyloxy)tryptamine (NOT).
NOT was also found to be several times more potent
than sumatriptan as a 5-HT1D agonist but inactive as
Debenzylation of racemic 5-(benzyloxy)-R-methyl-
1
5
24
a 5-HT1A agonist. We describe now a more detailed
investigation of 5-(alkoxy)tryptamines and related ana-
logs and their affinity for 5-HT1D receptors. Although
our work was initiated with bovine brain homogenate
binding assays (i.e., 5-HT1D receptors), cloned human
receptors (i.e., 5-HT1Dâ receptors) were utilized once
they became available. As a consequence, the use of
the cloned human receptors has allowed us to formulate
some limited structure-affinity relationships for the
binding of tryptamine analogues at 5-HT1Dâ receptors.
Selected compounds were also examined for binding at
tryptamine gave R-methyl-5-HT (29).
The O-alkyl
derivative 30 was prepared from the same starting
material by method B.
Compounds 31, 34, and 35 were prepared from the
common intermediate 42 (Scheme 1) which was, in turn,
prepared by the general procedure of King et al.1
Fischer cyclization of (4-methoxyphenyl)hydrazine with
N-phthalimido-4-aminocyclohexanone (41) provided 42,
which was N-deprotected to give 31 or O-deprotected
to give 43. Compound 43 was alkylated with 1-bro-
mononane or 1-bromohexane to give 34 and 35, respec-
tively, after deprotection via hydrazinolysis.
0,25
5
-HT1DR receptors.

3
16 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Glennon et al.
Sch em e 1a
Ta ble 3. Influence of Branching and Amine Substituents on
Receptor Affinity
a
b
HO
NH2
HO
NPhth
O
NPhth
R
CH2CH2N
CH2CHNH2
CH3
X
X
39
40
41
R′
c
N
H
N
H
NH2
NPhth
MeO
MeO
d
1
3–16, 27, 28
29, 30
N
H
N
H
Ki, nM (SEM)
5-HT1Dâ selecta
no.
X
R/R′
5-HT1A
31
42
1
1
3
4
(CH3)2CH(CH2)6O H/H
(CH3)3C(CH2)7O
1180(360) 14(3)
84
32
400
36
14
11
NH2
H/H
H/H
H/H
Me/Me
63(12)
920(80)
800(20)
575(45)
2.0(0.2)
2.3(0.8)
22(3)
e
NPhth
15 (CH ) C(CH ) O
RO
3
3
2 6
1
6
(C6H11)(CH2)4O
HO
f, g
27 CH (CH ) O
40(12)
3
2 8
N
2
8
CH3(CH2)8O
29 HO
CH3(CH2)8O
H/n-Bu 1550(190) 135(22)
N
250(20)
53(8)
H
3
0
3
3
4: R = (CH2)8CH3
5: R = (CH2)5CH3
H
a
5-HT1A Ki/5-HT1Dâ Ki value.
4
3
a
(a) PhthCOOEt/K2CO3/H2O; (b) PCC/CH2Cl2; (c) (p-methox-
yphenyl)hydrazine/HOAc; (d) H2N-NH2/EtOH/CHCl3; (e) BBr3/
Accordingly, we began to probe the previously defined
region of bulk tolerance associated with the indole
-position by examining a series of O-alkyl derivatives
CHCl3; (f) RBr/K2CO3/acetone; (g) H2N-NH2/EtOH/CHCl3.
5
Ta ble 2. Influence of the 5-Position Alkoxy Substituents on
of 5-HT (Table 2). Indeed, variation of alkyl chain
length from O-methyl to O-n-nonyl (i.e., 5-10) had little
effect on 5-HT1Dâ affinity, and all derivatives were
found to bind with an affinity comparable to that of
5-HT itself. These results support our previous hypoth-
esis concerning a region of bulk tolerance. Further-
more, 5-HT1A receptors also possess a region of bulk
tolerance, as reflected by the binding of 6-9, but a
region of bulk tolerance whose dimensions are evidently
different than that associated with 5-HT1Dâ receptors.
O-Alkyl substituents longer than n-octyloxy (i.e., 9) are
not readily accommodated by 5-HT1A receptors, and the
greatest difference is associated with the nonyloxy
compound 10.
Receptor Binding
CH2CH2NH2
CH3(CH2)nO
N
H
1
4
Ki, nM (SEM)
no.
n
5-HT1A
5-HT1Dâ
selectivitya
5
6
7
8
9
0
1
2
0
2
4
6
7
8
9
10
3.2(1.1)
88(29)
42(10)
38(5)
48(13)
315(15)
575(45)
885(145)
330(22)
3.5(0.9)
4.6(1.3)
1.6(0.7)
1.0(0.1)
3.0(1.7)
1.0(0.2)
35(15)
1
19
26
38
16
315
16
44
1
1
1
As a further probe of these regions of bulk tolerance,
we prepared several branched derivatives such as 13-
21(7)
10(2)
sumatriptan
33
1
6. The ω-dimethyl and cyclohexyl derivatives 13 and
a
5
-HT1A Ki/5-HT1Dâ Ki value; selectivity for 5-HT1Dâ sites.
16 display reduced affinity for 5-HT1Dâ receptors
relative to 5-HT (Table 3). It is noteworthy, nonethe-
less, that both 13 and 16 bind at 5-HT1Dâ receptors
with greater affinity and selectivity than tryptamine (4).
The ω-trimethyl derivative 14 retains 5-HT1Dâ affinity
but binds with unexpectedly high affinity for 5-HT1A
receptors. However, the ω-trimethyl derivative 15
retains the high 5-HT1Dâ affinity of 14 and displays
Resu lts a n d Discu ssion
O-Alk yl Der iva tives of Ser oton in . Tryptamine (4)
binds at 5-HT1D (5-HT1D Ki ) 23 nM, 5-HT1Dâ Ki )
3
6 nM) receptors with modest affinity and with little
selectivity over 5-HT1A receptors (Ki ) 91 nM). Sero-
tonin (1) binds with 10-fold higher affinity but with less
selectivity (5-HT1D Ki ) 2.2 nM, 5-HT1Dâ Ki ) 4.0 nM,
4
00-fold selectivity versus 5-HT1A receptors. As such,
1
5 is the most 5-HT1Dâ- versus 5-HT1A-selective agent
5
5
5
-HT1A Ki ) 1.7 nM). Thus, the presence of the
-position hydroxyl group enhances affinity both at
-HT1A and 5-HT1D/5-HT1Dâ receptors, but its pres-
reported to date.
Role of th e Eth er Oxygen for 5-HT1Dâ Bin d in g.
The binding of tryptamine (4) at 5-HT1D receptors
suggests that the 5-position oxygen atom of 5-HT (1) is
not critical for binding. Nevertheless, its presence does
seem to enhance affinity somewhat. Because the oxygen
atom appears to play a more important role for 5-HT1A
than for 5-HT1D binding, it was thought that 5-alkyl
derivatives of tryptamine might provide a new lead for
the development of 5-HT1D-selective agents. We began
by comparing the 5-HT1D affinity of O-methyl-5-HT (5)
and its N,N-dimethyl analogue 17 with that of the
corresponding pairs of compounds where the ether
oxygen atom had been replaced by a methylene group
(i.e., 18 and 19). Table 4 shows that the ether oxygen
ence seems to have a greater effect on 5-HT1A binding.
The hydroxy group may participate in hydrogen bond
formation with the receptors, but if it does, it likely
behaves as a hydrogen bond acceptor because O-methyl-
5
-HT (i.e., 5; Table 2) binds at 5-HT1Dâ (Ki ) 3.5 nM)
and 5-HT1A (Ki ) 3.2 nM) receptors with an affinity
comparable to that of 5-HT. This result is consistent
with our previous conclusion for 5-HT1D (bovine homog-
enate) binding,14 but is inconsistent with the recent
observation by Macor et al.11 that 5-methoxyindoles bind
with lower affinity than their corresponding hydroxy
derivatives.

Binding of O-Alkyl Derivatives of Serotonin
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 317
Ta ble 4. Role of the Ether Oxygen on 5-HT Receptor Affinity
Ta ble 5. Binding Affinities of Cyclic Tryptamine Analogues
CH2CH2NR2
X
NR2
X
X
N
R
N
N
N
H
H
H
Ki, nM (SEM)
3
1–36
37
no.
X
R
5-HT1A
3.2(1.1)
5-HT1Da 5-HT1Dâ
no.
X
R
5-HT1Dâ Ki, nM (SEM)
5
CH3O
CH3O
CH3CH2
CH3CH2
H
Me
H
Me
H
H
4.1(1.0)
20
3.5(0.9)
1
1
1
2
2
2
2
2
2
2
7
8
9
0
1
2
3
4
5
6
31
32
33
34
35
36
37
CH3O
CH3O
H
Me
H
H
H
342(26)
>1000a
10
172(12)
188(31)
>1000
>1000
20(6)
15(4)
7.8(1.8)
5.5(0.3)
275(35)
H2NC(O)
CH3(CH2)8CH2
CH3C(dO)
CH3C(dO)O
CH3CH2C(dO)O
(CH3)2CHC(dO)O Me
(CH3)3CC(dO)O Me
2300(200)
1.3(0.3)
CH3(CH2)8O
CH3(CH2)5O
CH3(CH2)8CH2
CH3(CH2)8O
9.7(2.1)
31(1)
7.4(1.4)
Me
H
Me
Me 405(6)
17(4)
98(17)
110(20)
59(1)
52(4)
63(5)
1.1(0.3)
a
Literature data,10 reported as pKD ) 8.0 using pig caudate
membrane homogenate.
CH3(CH2)7C(dO)O Me
9.3(0.8)
a
Homogenate binding data.
untoward effect on affinity;13 however, N-alkyl deriva-
tives possessing alkyl groups longer than n-propyl
typically bind with reduced affinity. 5-HT1D receptors
seem much more sensitive to the effect of small terminal
contributes little to the binding of these compounds (e.g.,
, 5-HT1Dâ Ki ) 3.5 nM; 18, Ki ) 7.8 nM). Thus, we
prepared and examined the chain-extended derivative
0 (i.e., the methylene counterpart of 10); surprisingly,
the affinity of 20 is 275-fold lower than that of 10. It
would seem that the oxygen atom plays more of a role
in the binding of longer chain compounds (such as 10)
than it does in the binding of simpler compounds such
as 18.
Focusing on the possible requirement of an oxygen
atom for optimal binding, we wondered if it was neces-
sary for the oxygen atom to be attached directly to the
aromatic nucleus or whether the electron density as-
sociated with this general location would be sufficient
for binding. Accordingly, we replaced the benzylic
methylene group of 18 (Ki ) 7.8 nM), or alternatively
the ether oxygen atom of 5 (Ki ) 3.5 nM), with a
carbonyl group; the resulting derivative, 21, was found
to bind at 5-HT1Dâ receptors with comparable affinity
5
14
amine substituents. In order to determine if this is
2
the case for 5-HT1Dâ receptors, we examined the N,N-
dimethyl and N-mono-n-butyl analogues of 10 (i.e., 27
and 28, respectively). Both compounds (27, Ki ) 40 nM;
2
8, Ki ) 135 nM; Table 3) bind with reduced affinity
relative to 10 itself (Ki ) 1.0 nM). Although this was
not the case with, for example, 18 versus 19, further
work with N-alkyl derivatives was abandoned.
R-Methylation of tryptamine derivatives results in a
14
5
0-60-fold decrease in 5-HT1D binding. In order to
evaluate this effect on 5-HT1Dâ binding, we examined
()-R-methyl-5-HT and (()-R-methyl-10 (29 and 30,
(
respectively). Compound 29 (Ki ) 250 nM; Table 3)
binds with 60-fold lower affinity than 5-HT itself; the
R-methyl derivative of 10 (30; Ki ) 53 nM) also binds
with reduced affinity. Thus, consistent with our previ-
14
ous 5-HT1D-derived SAR, substitution R to the ter-
(Ki ) 7.4 nM). We continued this investigation by
minal amine does not appear optimal for these types of
analogues.
examining a series of esters (i.e., derivatives that
contained two oxygen atoms; see below).
Cyclic An a logu es. Methyl substitution at the 2-po-
In an earlier investigation we found that N,N-disub-
stitution decreases the affinity of tryptamines for 5-HT1D
sition of 5-HT reduces 5-HT1D affinity by more than
14
4
00-fold. Elaboration of this methyl group to give the
1
4
receptors in bovine brain homogenate preparations;
see also 5 and 17 (Table 4). However, because the
-HT1Dâ affinity of 18 and 19 (Table 4) were nearly
cyclic derivatives 31 (Ki ) 342 nM) and 32 (Ki > 1000
nM; Table 5) also results in low-affinity compounds.
5
10
However, King et al. recently reported that carbazole
3 binds at 5-HT1D receptors with high affinity. Com-
identical, we continued by examining several additional
N,N-dimethyl derivatives. Compound 22, for example,
is the N,N-dimethyl ester analogue of 21. Compounds
3
pound 33 (pKD ) 8.0), a cyclic analogue of 5-carbam-
oyltryptamine (2; pKD ) 8.8), reportedly retains the
affinity of its uncyclized counterpart for pig caudate
2
2-25 bind at 5-HT1Dâ receptors with roughly similar
affinity (Ki ) 52-63 nM), supporting the concept of a
region of bulk tolerance. As with the compounds in
Table 2, we extended the length of the alkyl chain to
provide ester 26 (i.e., an ester whose chain length is
similar to that of 10). Ester 26 (Ki ) 1.1 nM) retained
the 5-HT1Dâ affinity of 10; however, it lacked 5-HT1Dâ
versus 5-HT1A selectivity.
The general conclusion is that although the ether
oxygen may not be necessary for the binding of shorter
chain compounds, its presence seems desirable for
optimal 5-HT1Dâ affinity and selectivity.
5
3
-HT1D receptors. Accordingly, we examine compounds
4 and 37 (carbazole and â-carboline derivatives of 10)
and 35 (a chain-shortened carbazole analogue). The
carboline 37 (Ki > 1000 nM) was inactive. The carba-
zoles 35 (Ki ) 188 nM) and 34 (Ki ) 172 nM) were found
to bind with low affinity. Indeed, 34 binds with >100-
fold lower affinity than its corresponding uncyclized
derivative 10. Compound 36, the methylene counter-
part of 34, is also inactive. At this time, it is not known
if these conflicting results reflect differing binding roles
of the indole 5-position substituents or differences
between porcine versus human 5-HT1D receptors. Nev-
ertheless, the low affinities of our cyclic analogues
suggest that the 2-position of the indole nucleus does
Effect of N-Alk yl a n d r-Alk yl Su bstitu en ts on
-HT1Dâ Bin d in g. 5-HT1A receptors allow the pres-
5
ence of relatively small terminal amine groups with no

3
18 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Glennon et al.
Ta ble 6. 5-HT1Dâ versus 5-HT1DR Binding Data on Selected
Thomas-Hoover melting point apparatus, are uncorrected.
Proton magnetic resonance spectra were obtained with a GE
QE-300, Bruker AC-300, or a Bruker AMX-500 spectrometer;
tetramethylsilane was used as an internal standard. Infrared
spectra were recorded on a Nicolet 5ZDX FT-IR. High-
resolution mass spectra were determined using a VG Analyti-
cal ZAB-SE mass spectrometer. Tetrahydrofuran and toluene
were dried by distallation with sodium metal. Elemental
analyses were performed by Atlantic Microlab Inc. (Norcross,
GA), and determined values are within 0.4% of theory except
where noted.
Compounds
5-HT1Dâ Ki, nMa
no.
5-HT1DR Ki, nM ((SEM)
select
1
4
5
7
8
0
1
2
3
5
6
0
7
8
1
4
5
4.0
36
1.7(0.3)
61(14)
0.4
1.7
1.5
0.9
4.9
1.6
0.7
3.3
3.0
7.0
2.5
0.8
1.0
1.7
3.5
13.6
5.8
3.5
1.6
1.0
1.0
65
21
14
2.3
22
275
40
5.4(0.6)
1.5(0.2)
4.9(2.2)
1.6(0.3)
42(8)
69(7)
42(9)
16(6)
55(5)
210(12)
42(1)
223(52)
1190(337)
2350(760)
1098(440)
1
1
1
1
1
1
2
2
2
3
3
3
3
-(2-Am in oet h yl)-5-(n -p en t yloxy)in d ole Oxa la t e (7).
Meth od A. A suspension of 5-(benzyloxy)tryptamine (1.9 g,
.13 mmol) in 10% HCl (30 mL) was treated with NaOAc (20
g), and the solution volume was adjusted to about 80 mL with
O. The mixture was allowed to stir at room temperature
7
H
2
135
342
172
188
for 30 min; a few pieces of ice chips were added followed by
acetic anhydride (20 mL), and the reaction mixture was
allowed to stir for 1 h. The precipitated materials were
collected and washed with H
recrystallized from CH Cl /hexane to give 1.6 g (74%) of
N-acetyl-5-(benzyloxy)tryptamine as a white solid, mp 133-
34 °C. A solution of this tryptamine (2.2 g, 7.13 mmol) in
2
O (2 × 20 mL), and the solid was
a
2
2
See text or previous tables for data; included here only for
purpose of comparison.
1
absolute EtOH (50 mL) was treated with Raney nickel (4.4 g)
in a Parr hydrogenation bottle and hydrogenated at 40 psi
overnight. The catalyst was removed by filtration through a
Celite pad, and the filtrate was concentrated under reduced
pressure to give an oil. The oil was purified by column
not readily allow substitution and/or that the tryptamine
side chain is in the wrong conformation for optimal
affinity.
5
-HT1Dâ vs 5-HT1Dâ Selectivity. To date, agents
chromatography using a solvent system of CH
1
2
Cl
0) to give 1.5 g (95%) of N-acetyl-5-HT as an oil.
A stirred mixture of N-acetyl-5-HT (0.45 g, 2.07 mmol),
-bromopentane (1.75 g, 11.59 mmol), anhydrous K CO (0.94
2
/MeOH (90:
are unknown that selectively bind to one population of
human 5-HT1D receptors over the other. In order to
determine if any of the present compounds might
display any selectivity, 16 were selected at random and
compared with 5-HT (1). Table 6 shows than none of
the compounds binds at one of the two populations with
more than 15-fold selectivity.
Su m m ar y. Sumatriptan (3) is a high-affinity 5-HT1D
ligand. In order to develop novel compounds with
similar affinity for 5-HT1D receptors but with reduced
affinity for 5-HT1A receptors, we explored the possibility
that substitution on the serotonin oxygen atom with
alkyl groups of differing length might impart enhanced
selectivity. Small O-alkyl groups are tolerated both at
1
2
3
g, 6.83 mmol), and MeOH (7 mL) in 2-butanone (40 mL) was
heated at reflux overnight under N . After being allowed to
2
cool to room temperature, the reaction mixture was filtered
and the filtrate was concentrated under reduced pressure to
give an oil. A solution of the oil in CH
successively with 2 N NaOH (1 × 30 mL) and H
mL). The organic portion was dried (MgSO ), and solvent was
2
Cl
2
(50 mL) was washed
2
O (1 × 30
4
removed under reduced pressure to give an oil. The oil was
purified by column chromatography using a solvent system of
CH Cl /MeOH (90:10) to give 0.53 g of the O-alkylated product
2
2
as an oil. Without further purification, the resulting oil in 2
N HCl (10 mL) was heated at reflux for 20 h. After the
reaction mixture was allowed to cool to room temperature, 2
N NaOH (20 mL) was added and the reaction mixture was
5
-HT1A and 5-HT1D receptors. Longer alkyl groups
seem to be better tolerated at 5-HT1D relative to
-HT1A receptors. Of the unbranched O-alkyl ana-
extracted with CH
portions were washed with H
MgSO ), and the solvent was removed under reduced pressure
to give an oil. The resulting oil was purified by column
chromatography using a solvent system of CH Cl /MeOH (90:
0). The combined fractions from the column were evaporated
under reduced pressure to give 0.16 g (31%) of 7 (free base) as
an oil. The oil in anhydrous Et O (5 mL) was added to a
2
Cl
2
(2 × 30 mL). The combined organic
5
2
O (1 × 30 mL) and dried
logues, the O-nonyloxy derivative 10 is optimal in terms
of affinity (Ki ) 1 nM) and selectivity (315-fold). Other
structural features were also examined in the present
investigation. For example, alkyl branching as with 15,
but not with 13, 14, or 16, can result in enhanced
selectivity. Alkyl substitution on the terminal amine,
and R-methylation, in the few cases examined, does not
result in enhanced affinity or selectivity. Conversion
of the O-alkyl substituents to esters, as with 22-26
results in compounds that bind; however, comparing 26
with 10, selectivity is reduced. Replacement of the
oxygen atom of 10 with a methylene group (i.e., 20)
results in reduced 5-HT1D affinity, as does cyclization
of 10 to a carbazole or â-carboline (e.g., 34, 37). The
most interesting agent described in this study is com-
pound 10; this prompted its disclosure in an earlier
communication in which it was described that 10
behaves as a 5-HT1D agonist with no 5-HT1A agonist
properties at the highest doses evaluated.15
(
4
2
2
1
2
saturated ethereal solution of oxalic acid. The resultant
oxalate salt was collected by filtration, washed with anhydrous
Et O (2 × 10 mL), and recrystallized from MeOH/Et O to give
2
2
a white solid, mp 145-147 °C. Anal. (C15
C, H, N.
H
22
N
2
2 2 4
O‚0.9C H O )
Compounds 6, 8, 9, and 12 were prepared in a similar
manner; see Table 1.
3
-(2-Am in oeth yl)-5-(n -n on yloxy)in d ole Hyd r och lor id e
(
10). Meth od B. Potassium carbonate (3.50 g, 25 mmol) was
added in one portion to a solution of N-t-BOC serotonin (38)
(3.95 g, 14 mmol) in MeCN (50 mL). Nonyl bromide (2.96 g,
14 mmol) was added via syringe, and the resulting reaction
mixture was allowed to stir under reflux conditions for 24 h.
After the reaction mixture had reached room temperature, the
solid material was removed by filtration and the solvent was
evaporated under reduced pressure. The crude product was
purified using flash chromatography with 25% EtOAc/hexanes
as eluent. The product (4.10 g, 73%) was recovered as a yellow/
Exp er im en ta l Section
Syn th esis. Column chromatography was performed on
silica gel (grade 62, 60-200 mesh, 150 Å). Merck grade 60
silica gel (230-400 mesh, 60 Å) or MN-silica gel 60 were used
for flash chromatography. Melting points, determined on a
brown oil which solidifed upon standing, mp 64-65 °C. HRMS
+
(EI): M for C24
38 2 3
H N O , calcd 402.2882, found 402.2861.
A solution of HCl (3 M) in EtOAc (50 mL) was added with
vigorous stirring to a solution of the above N-protected

Binding of O-Alkyl Derivatives of Serotonin
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 319
nonyloxy compound (4.00 g, 10 mmol) in EtOAc (10 mL). After
the reaction mixture was allowed to stir for 2 h (a white
precipitate formed after 5 min), solvent was evaporated under
reduced pressure and the product was triturated with anhy-
The solution was dried (MgSO
pressure to give an oil which was purified by column chroma-
tography using a solvent system of CH Cl /MeOH (9:1). The
combined fractions from the column were evaporated under
reduced pressure to afford 0.4 g (33.7%) of the desired
tryptamine as an oil. The oxalate salt was prepared and
4
) and evaporated under reduced
2
2
drous Et
washed well with anhydrous Et
.37 g (70%) of 10, mp 196-198 °C. A small portion of the
2
O. The solid product was collected by filtration and
2
O and then EtOAc to yield
2
recrystallized from MeOH/Et
mp 195-197 °C. Anal. (C12
2
O to afford 18 as a white solid,
‚0.5C ) C, H, N.
product was converted to the hydrogen oxalate salt, mp 149-
H
16
N
2
2 2 4
H O
1
5
1
50 °C (lit. mp 148-150 °C).
3-[2-(N,N-Dim eth yla m in o)eth yl]-5-eth ylin d ole Oxa la te
(19). A solution of oxalyl chloride (0.73 g, 5.79 mmol) in
Compounds 11 and 13-16 were prepared in a similar
manner (see Table 1).
anhydrous Et
2
O (10 mL) was added over a 5-min period to a
3
-(2-Am in oet h yl)-5-et h ylin d ole Oxa la t e (18). Solid
NaNO (3.16 g, 45.8 mmol) was added to a suspension of
-ethylaniline (5.0 g, 41.3 mmol) and concentrated HCl (17 mL)
solution of 5-ethylindole (0.7 g, 4.82 mmol) in anhydrous Et O
(20 mL) at 0 °C. The reaction mixture was stirred at room
temperature for 1h. The bright yellow precipitate was col-
2
2
4
in H
2
O (26 mL) under an ice-H
2
O bath. This solution was
lected by filtration, washed with anhydrous Et
and immediately added to a stirred solution of dimethylamine
(6 mL, 40% in H O) in H O (20 mL); stirring at room
temperature was allowed to continue overnight. The precipi-
tated material was collected by filtration, washed with H
O to
afford 0.92 g (78.1%) of the glyoxylamide as a light-yellow solid,
mp 177-178 °C. A suspension of the glyoxylamide (1.15 g,
4.71 mmol) and LiAlH (1.16 g, 30.6 mmol) in dry THF (50
4
2
O (2 × 20 mL),
kept at 0 °C with stirring while ethyl 2-methylacetoacetate
6.6 g, 45.8 mmol) in 95% EtOH (43 mL) was treated at 0 °C
with a solution of 50% KOH (16.5 mL) followed at once by ice
85 g). The diazo solution was then added immediately; the
reaction mixture was allowed to stir at room temperature for
h and was then extracted with Et
O (2 × 50 mL). The
combined Et O fractions were washed with H
O (2 × 50 mL)
and dried (MgSO ), and the solvent was removed under
(
2
2
(
2
O
(3 × 20 mL), air-dried, and recrystallized from MeOH/H
2
1
2
2
2
4
reduced pressure to give an oil. Absolute EtOH (33 mL)
saturated at 0 °C with anhydrous HCl gas was added to a
stirred solution of the oil in absolute EtOH (25 mL) at 0 °C.
The solution was heated at reflux for 30 min and then allowed
to stir at room temperature for 2 h. The suspension was
mL) was heated at reflux for 3 days under N
reaction mixture was allowed to cool to room temperature, the
LiAlH was decomposed by the addition of a saturated solution
of sodium potassium tartrate (7 mL) at 0 °C. The precipitated
material was removed by filtration, and the filtrate was dried
2
. After the
4
poured into cold H
2
O (200 mL) and was extracted with Et
O fractions were washed with
O (2 × 200 mL) and dried (MgSO ), and the solvent was
2
O
(MgSO
to afford an oily product which was purified by column
chromatography using a solvent system of CH Cl /MeOH (9:
1). The combined fractions from the column were evaporated
under reduced pressure to give an oil that solidified on
standing at room temperature. Without further purification,
4
). The solvent was removed under reduced pressure
(
H
2 × 200 mL). The combined Et
2
2
4
2
2
removed under reduced pressure to give a solid which was
recrystallized from CH Cl /hexane to provide 3.12 g (35%) of
a yellow solid, mp 98-99 °C. A suspension of this solid (0.34
g, 1.56 mmol) in 95% EtOH (5 mL) was added to a solution of
2
2
2
the free base was dissolved in anhydrous Et O (10 mL) and
KOH (0.66 g) in H
give a clear solution. The solution was acidified with glacial
acetic acid and poured into cold H O (40 mL). The solid was
washed well with H
O (2 × 10 mL) to give 0.29 g (98%) of
-ethylindole-2-carboxylic acid as a tan solid, mp 180-181 °C.
The mixture of the above acid (0.5 g, 2.64 mmol), freshly
2
O (2 mL) and heated at reflux for 1 h to
added to a saturated ethereal solution of oxalic acid. The
resultant oxalate salt was collected by filtration, washed with
2
anhydrous Et
Et O to afford 0.52 g (36%) of 19 as white needles, mp 178-
179 °C. Anal. (C14 ‚C ) C, H, N.
2
O (2 × 10 mL), and recrystallized from MeOH/
2
2
5
H
20
N
2
2 2 4
H O
3-(2-Am in oeth yl)-5-n -d ecylin d ole Hyd r och lor id e (20).
A solution of 4-n-decylaniline (3 g, 12.9 mmol) in dry toluene
distilled quinoline (5 mL), and copper chromite (0.1 g) was
immersed in an oil bath and heated at about 240 °C for 3 h
(30 mL) was added dropwise to a stirred solution of BCl
M in CH Cl , 35 mL) at 0 °C under N . The resultant solution
was allowed to stir for 5 min, and then chloroacetonitrile (5.1
mL, 79.3 mmol) and AlCl (3.5 g, 26.3 mmol) were added in
3
(1.0
under N
2
. The cooled brown syrup was poured into Et
2
O (50
2
2
2
mL); the solution was decolorized with activated carbon (Darco
G-60, 100 mesh), filtered, and washed successively with 2 N
HCl (4 × 20 mL) and 2 N NaOH (2 × 20 mL). The solution
3
succession in small portions. The mixture was heated at reflux
for 6 h and cooled on an ice bath, and HCl (2 N, 18 mL) was
added. The suspension was warmed on an oil bath at 70-72
°C for 45 min. NaOH (2 N) was added slowly with stirring to
the resultant hydrolyzed product to attain pH 6; during the
addition, the temperature was kept below 15 °C with an ice
bath. The layers were separated, and the aqueous phase was
was washed with H
activated carbon, filtered, and dried (MgSO ). The solvent was
2
O (3 × 20 mL), again decolorized with
4
removed under reduced pressure to give a yellow oil which as
purified [Kugelrohr, bp 73-80 °C (0.35 mmHg)] to give 0.26 g
(67.8%) of 5-ethylindole as a colorless oil.
A solution of oxalyl chloride (1.22 g, 9.59 mmol) in anhy-
drous Et
2
O (10 mL) was added over a 5-min period to a solution
O (20 mL)
extracted with CH
portions were dried (MgSO
2
Cl
2
(4 × 30 mL). The combined organic
of 5-ethylindole (1.16 g, 7.99 mmol) in anhydrous Et
2
4
), and solvent was evaporated
at 0 °C. The reaction mixture was allowed to stir at room
temperature for 1 h. The bright yellow precipitate was
under reduced pressure to give a brown residue. The crude
product was purified by chromatography using a solvent
system of EtOAc/hexane (1:9) to afford 0.39 g (9%) of a solid
collected by filtration, washed with anhydrous Et
2
O (2 × 20
mL), and immediately added to concentrated NH OH (20 mL)
4
material. NaBH
stirred solution of the solid (0.38 g, 1.22 mmol) in dioxane (3
mL) and H O (0.3 mL), and the mixture was heated at reflux
4
(0.093 g, 2.45 mmol) was slowly added to a
at 0 °C. The basic solution was allowed to stir at room
temperature for 4 h, and the solid was collected by filtration,
2
washed with H
from acetone to afford 1.4 g 81%) of glyoxylamide as a light
2
O (3 × 20 mL), air-dried, and recrystallized
for 6 h. The solvents were evaporated under reduced pressure
to give an oil. Water (10 mL) was added to the oil, and the
yellow solid, mp 230-233 °C. A suspension of the gloxylamide
mixture was extracted with CH
2
Cl
2
(3 × 25 mL). The
(1.36 g, 6.29 mmol) and LiAlH
4
(1.56 g, 40.9 mmol) in dry THF
. After the
combined CH Cl extracts were dried (MgSO
2
2
4
), and the solvent
(50 mL) was heated at reflux for 4 days under N
2
was evaporated under reduced pressure to give 0.28 g of a
crude oil which was purified by column chromatography using
a solvent system of hexane/CHCl (1:1) to afford 0.26 g (82%)
3
reaction mixture was allowed to cool to room temperature,
excess LiAlH was decomposed by the addition of a saturated
4
solution of sodium potassium tartrate (5 mL) at 0 °C. The
precipitated material was removed by filtration, and the
of 5-n-decylindole, mp 82-84 °C.
A solution of oxalyl chloride (0.15 g, 1.18 mmol) in anhy-
drous Et O (5 mL) was added dropwise to a solution of 5-n-
decylindole (0.25 g, 0.98 mmol) in anhydrous Et O (10 mL) at
filtrate was dried (MgSO
reduced pressure to afford an oily product which was dissolved
in Et
O (50 mL) and extracted with 2 N HOAc (3 × 20 mL).
The combined acid extracts were basified with 2 N NaOH. The
basic solution was extracted with Et
O (3 × 20 mL), and the
combined Et O extracts were washed with H
O (1 × 30 mL).
4
). The solvent was removed under
2
2
2
0 °C. The reaction mixture was allowed to stir at room
temperature for 1 h. The bright yellow precipitate was
collected by filtration, washed with hexanes (2 × 20 mL), and
2
2
2
4
immediately added to concentrated NH OH (10 mL) at 0 °C.

3
20 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Glennon et al.
The basic solution was allowed to stir at room temperature
for 4 h, and the solid was collected by filtration, washed with
solution (2 mL) at 0 °C. The mixture was filtered, and the
organic portion of the filtrate was washed with H
2
O (3 × 15
H
2
O (3 × 10 mL), air-dried, and recrystallized from methanol
mL) and dried (MgSO ). The solvent was removed under
4
to afford 0.20 g (66%) of the glyoxylamide as a light yellow
reduced pressure to afford a crude product. The oil was
chromatographed on a silica gel column (silica gel, 60 mesh)
solid, mp 205-208 °C. A solution of the glyoxylamide (0.1 g,
0
.31 mmol) and LiAlH
4
(0.08 g, 2.06 mmol) in dry THF (15
using a CHCl
the oil product with a saturated solution of oxalic acid in
anhydrous Et O gave 0.18 g (45%) of 28, mp 220-224 °C. Anal.
O‚C ) C, H, N.
(()5-(Non yloxy)-r-m et h ylt r yp t a m in e H yd r och lor id e
3 3
:CH OH (9:1) mixture as eluent. Treatment of
mL) was heated at reflux for 3 days under N
the reaction mixture to cool to room temperature, excess
LiAlH was decomposed by the addition of a saturated solution
2
. After allowing
2
4
(C23
H
38
N
2
2 2 4
H O
of sodium potassium tartrate (1 mL) at 0 °C. The precipitated
material was removed by filtration, and the filtrate was dried
2
4
(30). A mixture of (()-5-(benzyloxy)-R-methyltryptamine
(MgSO
4
). The solvent was removed under reduced pressure
(0.56 g, 2.0 mmol) and di-tert-butyl dicarbonate (0.44 g, 2.0
to afford an oily product which was purified by column
mmol) in EtOAc (20 mL) was allowed to stir at room temper-
chromatography using a solvent system of CH
2
Cl
2
/MeOH (9:
O gave 33
ature for 24 h under N
× 30 mL) and H O (3 × 3 mL). The organic portion was dried
(MgSO ) and evaporated to dryness under reduced pressure
2
and was then washed with 5% HCl (2
1
). The free base was converted to the hydrochloride salt;
2
recrystallization of the crude salt from MeOH/Et
2
4
mg (30%) of 20 as a white solid, mp 198-200 °C. Anal.
‚HCl‚0.5H O) C, H, N.
-[2-(N,N-Dim eth yla m in o)eth yl]-5-[(n -octylca r bon yl)-
oxy]in d ole Oxa la te (26). A stirred mixture bufotenine
hemioxalate (297 mg, 1 mmol), octanoyl chloride (195 mg, 1.2
to give 0.67 g (88%) of the product as an oil. A solution of the
oil (0.76 g, 2.0 mmol) in MeOH (50 mL) containing 10% Pd/C
(0.25 g) was hydrogenated in Parr apparatus at 40 psi for 12
h. The reaction mixture was filtered, and the filtrate was
evaporated under reduced pressure to give 0.44 g (76%) of (()-
5-hydroxy-N-t-BOC-R-methyltryptamine as a yellow/brown
foam, mp 60-62 °C. A mixture of this protected amine (0.58
(C
20
H
32
N
2
2
3
mmol), and NEt
was heated at reflux for 8 h under N
3
(177 mg, 3 mmol) in dry benzene (15 mL)
After the reaction
2
.
mixture was allowed to cool to room temperature, it was
filtered, and the filtrate was concentrated under reduced
g, 2.0 mmol), 1-bromononane (0.62 g, 3.0 mmol), and K
(0.41 g, 3.0 mmol) in MeCN (20 mL) was heated at reflux for
24 h under N with stirring. After the reaction mixture was
2 3
CO
pressure to give an oil. The oil was taken up in CH
mL) and washed with 0.2 N NaOH (2 × 20 mL) and H
0 mL). The organic portion was dried (MgSO ), and the
solvent was removed under reduced pressure to give an oil
which was purified by column chromatography (8:2 CH Cl
MeOH). The oil in anhydrous Et O (5 mL) was added to a
2
Cl
2
(50
2
2
O (2 ×
cooled to room temperature, the solid was removed by filtration
and the solvent evaporated under reduced pressure to give 0.47
g of an oily product. The oil was purified by column chroma-
tography (25% EtOAc/hexane) to give 0.34 g (62%) of product
as an oil. A solution of 3 N HCl in EtOAc (15 mL) was added
to a solution of (()-5-(nonyloxy)-N-t-BOC-R-methyltryptamine
(0.42, 1.0 mmol) in EtOAc (5 mL). The mixture was allowed
to stir for 2 h. The precipitated product was collected by
2
4
2
2
/
2
saturated ethereal solution of oxalic acid (10 mL). The
resultant salt was collected by filtration, washed with anhy-
drous Et
2 2
O, and recrystallized from MeOH/Et O to afford 226
mg (56% yield) of 26 as a white solid, mp 135-137 °C. Anal.
filtration and washed with EtOAc (2 × 15 mL) and Et O (2 ×
2
(C
21
H
32
N
2
O
2
‚C
2
H
2
O
4
‚H
2
O) C, H, N.
15 mL). An analytical sample was prepared by recrystalliza-
3
-[2-(N ,N -Dim e t h yla m in o)e t h yl]-5-[(n -n on yloxy)in -
tion from 1-propanol to give 0.28 g (78%) of 30, mp 201-202
d ole Oxa la te (27). Sodium cyanoborohydride (0.13 g, 2.1
mmol) was added to a stirred solution of 10 (free base; 0.22 g,
°C. Anal. (C20
H
32
N
2
2
O‚HCl‚0.5H O) C, H, N.
(()3-Am in o-6-m eth oxy-1,2,3,4-tetr ah ydr ocar bazole (31).
0
.7 mmol) and CH
2
O (37%; 0.21 g, 0.7 mmol) in MeCN (7 mL).
Hydrazine hydrate (0.10 g, 1.99 mmol) was added via syringe
Glacial HOAc (0.07 mL) was added, and stirring was allowed
to continue; after 2 h, additional HOAc (0.07 mL) was added,
and the reaction mixture was allowed to stir for 30 min. The
3
to a solution of 42 (0.345 g, 1.0 mmol) in CHCl (10 mL);
absolute EtOH (15 mL) was then added via syringe. The
reaction mixture was allowed to stir overnight at room
temperature, cooled to 0 °C, and filtered, and the solid material
reaction mixture was poured into Et
was washed with 1 N KOH (3 × 10 mL) and brine (10 mL),
dried (K CO ), and evaporated to dryness under reduced
2
O (50 mL). The solution
was washed with small amounts of cold CHCl
3
. The combined
2
3
solvent was removed under reduced pressure to give 0.18 g
1
pressure to give 0.24 g of residue. This solid material was
purified by column chromatography (silica gel, 60 mesh) using
MeOH as eluent to give 0.06 g (25%) of 27 (free base) as an
oil. The oxalate salt was prepared and recrystallized from
3
(83%) of 31 as a yellow solid: H NMR (CDCl , 500 MHz) δ
1.6 (br s, 1H), 1.74-1.80 (m, 1H), 2.02-2.06 (m, 1H), 2.41-
2.46 (m, 1H), 2.78 (t, J ) 6.35 Hz, 2H), 2.98 (ddd, J ) 14.9,
5.1, 1.1 Hz, 1H), 3.27-3.29 (m, 1H), 3.84 (s, 3H), 6.76 (dd, J )
absolute EtOH/anhydrous Et
2
O to afford 27 as a white solid,
O‚C ‚0.25 H O) C, H,
8.7, 2.5 Hz, 1H), 6.91 (d, J ) 2.5 Hz, 1H), 7.13 (d, J ) 8.7 Hz,
+
mp 128-131 °C. Anal. (C21
H
34
N
2
2
H
2
O
4
2
1H), 7.85 (s, 1H); HRMS (FAB) MH calculated for C13
217.1341, found 217.1310.
16 2
H N O
N.
3
-[2-(N-Bu t yla m in o)et h yl]-5-(n -n on yloxy)in d ole Ox-
(()3-(N,N-Dim eth yla m in o)-6-m eth oxy-1,2,3,4-tetr a h y-
d r oca r ba zole Oxa la te (32). The free base of compound 32
was obtained as a gift from Dr. A. Mooradian (Sterling-
Winthrop Research Institute, Rensselaer, NY)26 and converted
to its oxalate salt, mp 195-197 °C (95% EtOH). Anal.
a la te (28). A solution of butyryl chloride (0.12 g, 1 mmol) in
THF (3 mL) was added dropwise to a stirred solution of 10
free base; 0.33 g, 1 mmol) and Et
(
(
3
N (0.16 g, 2 mmol) in THF
10 mL) at 0 °C (ice bath). The reaction mixture was allowed
to stir overnight at room temperature. The white precipitate
Et N‚HCl) was removed by filtration and washed well with
THF (2 × 5 mL), and the combined filtrate and washings were
evaporated under reduced pressure. The oily residue in CHCl
10 mL) was washed successively with 5% HCl (20 mL), 5%
Na CO solution (30 mL), and H O (30 mL). The CHCl
portion was dried (MgSO ), and the solvent was removed under
(C15
H
20
N
2
2 2 4
O‚C H O ) C, H, N.
(
3
(()3-Am in o-6-(n -n on yloxy)-1,2,3,4-t et r a h yd r oca r b a -
zole (34). Potassium carbonate (0.17 g, 1.24 mmol) and
1-bromononae (0.13 g, 0.62 mmol) were added to a solution of
43 (0.21 g, 0.62 mmol) in anhydrous acetone (30 mL). The
resulting solution was heated at reflux for 48 h. The solid was
removed by filtration and the solvent removed under reduced
pressure. The product (0.23 g, 81%) was isolated as a yellow
oil. Due to the instability of this compound, the phthalimide
group was removed and full characterization was performed
only on the free amine. Deprotection was carried out as
described for the preparation of 31. The free amine was
3
(
2
3
2
3
4
reduced pressure to afford 0.33 g (83%) of a yellow, oily
intermediate amide. The compound was promptly used in the
next step without further characterization. AlH
by the careful addition of AlCl (0.2 g, 1.5 mmol) to a
suspension of LiAlH (0.2 g, 5.2 mmol) in anhydrous Et O (15
mL) at 0 °C, under N . The suspension was allowed to stir
for 30 min at room temperature, and then a solution of the
above amide (0.33 g, 0.9 mmol) in anhydrous Et O (10 mL)
was added in dropwise manner. The reaction mixture was
allowed to stir for 5 h at room temperature. Excess AlH was
decomposed by the addition of crushed ice (1 g) and 20% NaOH
3
was prepared
3
4
2
2
isolated in quantitative yield as a white solid: mp 105-107
1
°C dec; H NMR (MeOH-d
4
, 500 MHz) δ 0.9 (t, J ) 7 Hz, 3H),
2
1.28-1.40 (m, 10H), 1.45-1.50 (m, 2H), 1.73-1.78 (m, 2H),
1.94-1.97 (m, 1H), 2.18-2.2 (m, 1H), 2.61 (dd, J ) 14.8, 8.6
Hz, 1H), 2.86-2.87 (m, 2H), 3.07 (dd, J ) 14.5, 5.0 Hz, 1H),
3.48-3.50 (m, 1H), 3.96 (t, J ) 6.5 Hz, 2H), 6.69 (dd, J ) 8.7,
3

Binding of O-Alkyl Derivatives of Serotonin
.4 Hz, 1H), 6.85 (d, J ) 2.4 Hz, 1H), 7.12 (d, J ) 8.7 Hz, 1H);
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 321
EtOAc portion was dried (MgSO ) and evaporated to dryness
2
4
+
HRMS (FAB) MH calculated for C21
29.2579.
()-3-Am in o-6-(h e xyloxy)-1,2,3,4-t e t r a h yd r oca r b a -
H
32
N
2
O 329.2593, found
to give 3.8 g (93%) of a yellow/brown foam, mp 52-54 °C.
+
3
HRMS (EI): M for C15
1476.
20 2 3
H N O , calcd 276.1474, found 276-
(
zole (35). This compound was prepared following the same
procedure used for the preparation of 34. 1-Bromohexane was
used in the place of 1-bromononane. The product was isolated
N-P h a th a lim id o-tr a n s-4-a m in ocycloh exa n ol (40). Po-
tassium carbonate (8.01 g, 58 mmol) followed by N-carbethoxy-
phthalimide (8.01 g, 37 mmol) was added to a solution of trans-
4-aminocyclohexanol (39) (5.04 g, 33 mmol) in H O (75 mL).
2
A white precipitate formed immediately, which after stirring
1
as a white solid in 65% yield: mp 217-219 °C dec; H NMR
(
6
2
(
(
DMSO-d
6
, 500 MHz) δ 0.9 (t, J ) 7 Hz, 3H), 1.28-1.32 (m,
H), 1.40-1.45 (m, 2H), 1.65-1.71 (m, 2H), 1.85-1.93 (m, 1H),
at room temperature for 30 min was collected to give 6.97 g
1
.12-2.2 (m, 1H), 2.60 (dd, J ) 15.0, 8.9 Hz, 1H), 2.78-2.79
(86%) of 40, mp 177-178 °C. H NMR (CDCl
3
, 200 MHz): δ
m, 2H), 2.99 (dd, J ) 15.0, 5.2 Hz, 1H), 3.36 (br s, 1H), 3.92
t, J ) 6.5 Hz, 2H), 6.64 (dd, J ) 8.7, 2.4 Hz, 1H), 6.83 (d, J )
1.42 (qd, J ) 13.5, 3.3 Hz, 2H), 1.71 (dd, J ) 12.7, 2 Hz, 2H),
1.79 (s, 1H), 2.08 (dd, J ) 12.7, 2 HZ, 2H), 2.32 (qd, J ) 13.1,
2
.4 Hz, 1H), 7.12 (d, J ) 8.7 Hz, 1H), 8.01 (s, 1H); HRMS (FAB)
3.4 Hz, 2H), 3.75 (m, 1H), 4.12 (m, 1H), 7.64-7.82 (m, 4H);
+
+
MH calculated for C18
-Am in o-6-n -decyl-1,2,3,4-tetr ah ydr ocar bazole Oxalate
36). A solution of NaNO (0.6 g, 8.56 mmol) in H O (3 mL)
H
26
N
2
O 287.2123, found 287.2111.
HRMS (EI) M calculated for C14
245.1051.
3
H15NO 245.1052, found
3
(
2
2
(()-N-P h th a lim id o-4-a m in ocycloh exa n on e (41). Mo-
lecular sieves (4 Å, 15 g), followed by PCC (11.5 g, 53 mmol),
was added to a solution of 40 (5.23 g, 21 mmol) in CH Cl (100
2 2
mL). The reaction became dark green in color and was stirred
for 3 h. The entire reaction mixture was transferred to a silica
gel column (4 in.) and eluted with EtOAc. The solvent was
was added to a stirred solution of 4-n-decylaniline (2 g, 8.56
mmol) in concentrated HCl (8 mL) at -10 °C. The mixture
was stirred at 0 °C for 0.1 h and was then added portionwise
to a cooled (-10 °C) and stirred solution of SnCl
2
2
‚2H O (7.25
g, 32 mmol) in concentrated HCl (4.8 mL), during which time
the temperature was maintained below -5 °C. The resulting
cream-colored suspension was warmed to 25 °C, filtered, and
evaporated under reduced pressure to give 4.85 g (95%) of 41
1
as a white solid: H NMR (CDCl
3
, 200 MHz) δ 2.0 (m, 2H),
washed with Et
2
O (3 × 10 mL). The product was recrystallized
2.45 (m, 4H), 2.6-2.8 (m, 2H), 4.6 (m, 1H), 7.6-7.9 (m, 4H).
Compound 41 was used without further characterization.
(()-N-P h th a lim id o-3-a m in o-6-m eth oxy-1,2,3,4-tetr a h y-
d r oca r ba zole (42). A solution of 1 N NaOH (32 mL, 32
mmol) was added to a solution of (4-methoxyphenyl)hydrazine
from absolute EtOH to afford 1.8 g (75%) of (4-decylphenyl)-
hydrazine hydrochloride as a white solid, mp 193-195 °C. A
2
5
solution of N-phthalimido-4-aminocyclohexanone (41) (0.4 g,
1
.64 mmol) in EtOH (10 mL) was added to a stirred solution
of this solid (0.47 g, 1.64 mmol) in EtOH (10 mL). The reaction
mixture was heated at reflux for 2 h. The precipitate was
collected by filtration and recrystallized from methanol to
afford 0.60 g (80%) of 6-n-decyl-3-phthalimimido-1,2,3,4-tet-
rahydrocarbazole as a white solid, mp 100-102 °C.
Hydrazine hydrate (7.5 mL) was added to the carbazole (0.5
g, 1.09 mmol) in absolute EtOH (30 mL). The reaction mixture
was heated at reflux for 2 h. The solvent was removed under
reduced pressure, and the oily residue was dissolved in EtOAc
2
hydrochloride (5.01 g, 29 mmol) in H O (100 mL). A precipi-
tate formed immediately, and the reaction was allowed to stir
at room temperature for 15 min. The product was extracted
into CHCl
were dried (MgSO
3
(3 × 75 mL), and the combined organic portions
4
) and evaporated to dryness under reduced
pressure to give the free hydrazine as a yellow solid (2.89 g,
72%). Solid (4-methoxyphenyl)hydrazine (2.89 g, 21 mmol)
was added in one portion to a solution of N-phthalimido-trans-
4-aminocyclohexanone (41; 5.09 g, 21 mmol) in HOAc (100
mL). The solution was heated at reflux for 2 h and then cooled
(
H
50 mL), washed successively with 10% NaHCO
O (10 mL), and dried Mg(SO ). The solvent was removed
under reduced pressure to give a white solid. An anhydrous
Et O solution of the amine was treated an with Et O solution
of oxalic acid to afford the crude salt; recrystallization from
MeOH/anhydrous Et O gave 93 mg (20%) of 36 as a white
3
(5 mL) and
2
4
to room temperature and poured into H
product was extracted into CHCl , and the combined organic
portions were washed with H O (100 mL), 1% NaHCO (100
mL), and brine (100 mL), then dried (MgSO ), and evaporated
to dryness under reduced pressure to give 42 as a yellow solid
2
O (200 mL). The
3
2
2
2
3
4
2
1
solid, mp 205-208 °C. Anal. (C22
H, N.
H
34
N
2
‚C
2
H
2
O
4
‚O.5H
2
O) C,
3
(6.98 g, 96%), mp 211-213 °C. H NMR (CDCl , 300 MHz):
δ 2.82-3.0 (m, 4H), 3.43-3.52 (m, 2H), 3.82 (s, 3H), 4.62-
4.72 (m, 1H), 6.79 (dd, J ) 8.8, 2.2 Hz, 1H), 6.86 (d, J ) 2.2
Hz, 1H), 7.18 (d, J ) 8.8 Hz, 1H), 7.73 (dd, J ) 5.5, 2.9 Hz,
6
-(n -Non yloxy)-2-m eth yl-1,2,3,4-tetr a h yd r o-9H-p yr id o-
[
3,4-b]in d ole Oxa la t e (37). Formic acid (88%, 0.14 g, 3.1
mmol), followed by formaldehyde (36%, 0.20 g, 6.7 mmol), was
slowly added to 3-(2-aminoethyl)-5-(n-nonyloxy)indole (0.36 g,
2H), 7.76 (s, 1H), 7.86 (dd, J ) 5.5, 2.9 Hz, 2H); HRMS (FAB):
+
MH calculated for C21
H
18
N
2
O
3
347.1396, found 347.1375.
1
8
mmol) at 0 °C. The resulting solution was allowed to stir at
0 °C for 24 h, cooled to 0 °C, and acidified with 6 N HCl (1
(()-N-P h th a lim id o-3-a m in o-6-h yd r oxy-1,2,3,4-tetr a h y-
d r oca r ba zole (43). Boron tribromide (3.93 mL of a 1 M
mL). The mixture was extracted with Et
basified to pH 11 by the addition of 20% aqueous NaOH, and
extracted with Et
O (3 × 10 mL). The pooled ether extracts
were washed with H O (5 mL) and dried (MgSO ), and solvent
was removed under reduced pressure. The resulting residue
was purified using column (250 mL volume) chromatography
2
O (3 × 10 mL),
solution in CH
solution of 42 (0.80 g, 2.31 mmol) in anhydrous CH
2
Cl
2
, 3.93 mmol) was added under argon to a
Cl (20
2
2
2
mL) at -78 °C. The reaction mixture was allowed to stir at
2
4
-78 °C for 2 h and then at room temperature overnight. The
2
dark solution was poured into H O (100 mL), and the product
was extracted into EtOAc (2 × 100 mL). The combined organic
on silica gel (62 mesh), eluting with CHCl
followed by preparation of the oxalate salt, to afford 0.19 g
44%) of 37 as a white solid after recrystallization from
3
:CH
3
OH (9:1),
portions were washed with brine, dried (MgSO ), and evapo-
4
rated to dryness under reduced pressure. The residue was
purified by flash column chromatography (using 1:1 hexanes:
EtOAc as eluent). Carbazole 43 was obtained as a yellow solid
(
1
absolute EtOH/anhydrous Et
DMSO-d ) δ 0.8-0.9 (t, 3H, CH
.8 (m, 2H, CH ), 2.8-3 (m, 5H, CH
.9-4.0 (t, 2H, OCH ), 4.4 (s, 2H, CH
.9 (d, 1H, Ar), 7.2-7.3 (d, 1H, Ar). Anal. (C21
.5C ) C, H, N.
N-t-BOC-ser oton in (38). Potassium carbonate (4.1 g, 30
mmol) was added all at one time to a suspension of serotonin
creatinine sulfate monohydrate (6.0 g, 15 mmol) in H O (75
2
O: mp 220-224 °C; H NMR
), 1.1-1.5 (m, 12H, CH ), 1.6-
NCH ), 3.5 (m, 2H, CH ),
), 6.7-6.8 (dd, 1H, Ar),
O‚
1
(
6
3
2
(0.152 g, 20%), mp 270 °C dec. H NMR (DMSO-d
6
, 200
1
3
6
0
2
2
3
2
MHz): δ 2.65-2.92 (m, 4H), 3.1-3.28 (m, 2H), 4.45-4.49 (m,
2
2
1H), 6.53 (dd, J ) 8.5, 2.2 Hz, 1H), 6.65 (d, J ) 2.2 Hz, 1H),
H
32
N
2
7.06 (d, J ) 8.5 Hz, 1H), 7.90 (s, 4H), 8.56 (s, 1H), 10.5 (s,
+
2
H
5
O
4
1H). HRMS (EI): M calculated for C20
found 332.1144.
16 2 3
H N O 332.1162,
Ra d ioliga n d Bin d in g Assa y. The polymerase chain reac-
tion (PCR) was used to amplify and clone human 5-HT1DR
and 5-HT1Dâ subtype genes based upon published sequences.
The nucleotide sequences were verified by sequencing the
DNA, and then both of the genes were subcloned into expres-
sion vectors, pcDNA1/Amp and pRc/CMV (Invitrogen). Ex-
pression of each gene was confirmed by the transient trans-
fection of COS-1 cells using the pcDNA1/Amp construct.
2
mL); once the solid material had dissolved, di-tert-butyl
dicarbonate (3.2 g, 15 mmol) was added via syringe, and the
resulting mixture was allowed to stir at room temperature for
2
4 h. The product was extracted with EtOAc (3 × 75 mL),
and the combined organic fraction was washed with H
O (1 ×
0 mL), 5% HCl (1 × 50 mL), and brine (1 × 50 mL). The
2
5

3
22 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Glennon et al.
Stable cell lines of each receptor subtype were generated by
transfecting CHO and/or HEK 293 cells with the pRc/CMV
construct using lipofectin-mediated DNA transfection (GIB-
CO). G418-resistant clones were screened for expression using
reverse transcription of RNA followed by PCR. All ligand
binding studies were performed on membranes from tran-
siently or stably expressing cells.
(11) Macor, J . E.; Blank, D. H.; Fox, C. B.; Lebel, L. A.; Newman, M.
E.; Post, R. J .; Ryan, K.; Schmidt, A. W.; Schulz, D. W.; Koe, B.
K. 5-[(3-Nitropyrid-2-yl)amino]indoles: Novel serotonin agonists
with selectivity for the 5-HT1D receptor. Variation of the C3
substituent on the indole template leads to increased 5-HT1D
receptor selectivity. J . Med. Chem. 1994, 37, 2509-2512.
(12) Clitherow, J . W.; Scopes, D. I. C.; Skingle, M.; J ordan, C. C.;
Feniuk, W.; Campbell, I. B.; Carter, M. C.; Collington, E. W.;
Connor, H. E.; Higgins, G. A.; Beattie, D.; Kelly, H. A.; Mitchell,
W. L.; Oxford, A. W.; Wadsworth, A. H.; Tyers, M. B. Evolution
of a novel series of [(N,N-dimethylamino)propyl]- and piperazi-
nylbenzanilides as the first selective 5-HT1D antagonists. J .
Med. Chem. 1994, 37, 2253-2257.
Radioligand binding studies were performed using mem-
brane homogenates prepared from cells transfected with the
human 5-HT1A, 5-HT1DR, or 5-HT1Dâ genes as previously
2
7
described. 5-HT1D binding studies were performed using
2
8
calf striatum homogenates as previously described. 5-HT1A
(13) Glennon, R. A. Concepts for the design of 5-HT1A agonists and
antagonists. Drug Dev. Res. 1992, 26, 251-274.
3
receptors were labeled with 0.2 nM [ H]-8-OH-DPAT. 5-HT1DR
3
and -â receptors were labeled with 2 nM [ H]-5-HT. Mem-
(14) Glennon, R. A.; Ismaiel, A. M.; Chaurasia, C.; Titeler, M.
5
-HT1D receptors: Results of a structure-affinity investigation.
brane homogenates, radioligands, and competing drugs were
incubated at 37 °C for 30 min, followed by rapid filtration
through Schleicher & Schuell glass-fiber filters, and counted
in ecoscint cocktail in a Beckman 3801 liquid scintillation
counter.
Drug. Dev. Res. 1991, 22, 25-36.
(
15) Glennon, R. A.; Hong, S.-S.; Dukat, M.; Teitler, M.; Davis, K.
5
-(Nonyloxy)tryptamine: A novel high-affinity 5-HT1Dâ sero-
tonin receptor agonist. J . Med. Chem. 1994, 37, 2828-2830.
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Chem. Soc. 1974, 96, 7101-7103.
(17) Cason, J . Branched chain fatty acids. I. Synthesis of 17-
methyloctadecanoic acid. J . Am. Chem. Soc. 1942, 64, 1106-
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