Influence of chain length and N-alkylation on the selective serotonin receptor ligand 9-(aminomethyl)-9,10-dihydroanthracene

Article abstract of DOI:10.1016/S0960-894X(01)00023-3

Comparison of the serotonin 5-HT_2A receptor affinities of chain lengthened and N-alkylated analogues of the novel ligand 9-aminomethyl-9.10-dihydroanthracene (AMDA) and a structurally similar prototypical tricyclic amine imipramine suggests that the two agents bind to the receptor in different fashions. The demonstration that AMDA is highly selective for serotonin receptors (5-HT_2A, K_i = 20 nM: 5-HT_2C, K_i = 43 nM) versus the dopamine D₂ receptor (K_i > 10,000 nM). as well as the serotonin and norepinephrine transporters (K_i >10.000nM) further suggests that AMDA and the nonselective ligand imipramine interact with these target macromolecules in different ways.

Full text of DOI:10.1016/S0960-894X(01)00023-3

Bioorganic & Medicinal Chemistry Letters 11 (2001) 655±658
In¯uence of Chain Length and N-Alkylation
on the Selective Serotonin Receptor Ligand
9
-(Aminomethyl)-9,10-dihydroanthracene
a
b,c
a
b,c
Scott P. Runyon, Jason E. Savage, Mohamed Taroua, Bryan L. Roth,
a,
a
Richard A. Glennon and Richard B. Westkaemper *
aDepartment of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, R.B. Smith Building,
4
10 North 12th Street, PO Box 980540, Richmond 23298-0540, VA 23298, USA
b
Departments of Biochemistry and Psychiatry, Case Western Reserve University School of Medicine,
Cleveland, OH 44106, USA
c
The NIMH Psychoactive Drug Screening Program, USA
Received 17 July 2000; accepted 28 December 2000
AbstractÐComparison of the serotonin 5-HT2A receptor anities of chain lengthened and N-alkylated analogues of the novel
ligand 9-aminomethyl-9,10-dihydroanthracene (AMDA) and a structurally similar prototypical tricyclic amine imipramine suggests
that the two agents bind to the receptor in di€erent fashions. The demonstration that AMDA is highly selective for serotonin
receptors (5-HT2A, K =20 nM; 5-HT2C, K =43 nM) versus the dopamine D receptor (K >10,000 nM), as well as the serotonin and
i i 2 i
norepinephrine transporters (K >10,000 nM) further suggests that AMDA and the nonselective ligand imipramine interact with
i
these target macromolecules in di€erent ways. # 2001 Elsevier Science Ltd. All rights reserved.
We have recently described 9-(aminomethyl)-9,10-dihy-
droanthracene (AMDA, 1a) as the parent member of a
potentially new class of 5-HT2A receptor antagonists.
cal tricyclic amine class, cyproheptadine (2), probably
3
bind to 5-HT2A receptors in di€erent fashions.
1
With the exception of its two aromatic rings and basic
nitrogen, it is remarkably devoid of the pharmacophore
features usually associated with selective, high anity
receptor ligands. Although AMDA was initially con-
ceived and evaluated to test a theoretical receptor model
without explicit consideration of other known 5-HT
2
ligands, it became apparent that the 9-(aminomethyl)-
9
,10-dihydroanthracene nucleus bears a general simi-
larity to at least two classes of known, nonselective ser-
otonin receptor ligands: tricyclic antidepressants and
antipsychotic agents. Both classes of agents are tricyclic
amines consisting of two aromatic groups ¯anking a
non-aromatic central ring that bears an alkylamino
substituent as in AMDA. If AMDA were to share a
common mode of binding with either class, given the
multiple neurochemical actions of classical tricyclic
amines, enthusiasm for further development based on
the AMDA skeleton would be signi®cantly diminished.
We have recently demonstrated that AMDA and a
conformationally restricted representative of the classi-
Cyproheptadine is a useful model to study potential
similarities and di€erences between classical tricyclic
amines and AMDA derivatives, principally because it is
a relatively rigid structure. However, most clinically
useful classical tricyclic amines are conformationally
¯exible. Since chain length and N-alkylation are two
*Corresponding author. Fax: +1-804-828-7625; e-mail: richard.
westkaemper@vcu.edu
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00023-3

656
S. P. Runyon et al. / Bioorg. Med. Chem. Lett. 11 (2001) 655±658
major structural features that clearly distinguish
AMDA from conformationally ¯exible classical tricyclic
amines, we investigated the in¯uence of chain length
and N-alkylation in the AMDA series compared to
imipramine (3c), a prototypical, nonselective, con-
formationally ¯exible tricyclic amine. To this end, we
synthesized, examined geometric properties of, and
evaluated chain lengthened and N-alkylated analogues
of AMDA and demethylated derivatives of imipramine
for comparison.
simulations of imipramine suggest that folded con-
formers with decreased phenyl-to-N distances (range
Ê
7
4.0±7.5 A) do occur. Thus, classical tricyclic amines can
attain an AMDA-like con®guration. The series, where
n=0±3, includes the `phenylethylamine' skeleton of
AMDA and the `phenylbutylamine' skeleton of imipra-
mine. Anity is highest for the phenylethylamine and
`phenylbutylamine' skeletons. Interpreted in terms of
receptor binding modes, there are two limiting possibi-
lities. AMDA (1a) and 6a might bind in a similar fash-
ion with 6a attaining an AMDA-like conformation.
Alternatively, the aromatic moieties of AMDA and 6a
might occupy di€erent regions of the receptor allowed
or enforced by the extension of the 6a side chain, that is
6a binds in a manner similar to imipramine. Since dif-
ferent classes of 5-HT2A ligands show di€erent e€ects
The data suggest (Table 1) that there may be two opti-
mal chain lengths for high 5-HT2A receptor anity in
the AMDA series. These are represented by an embed-
ded phenylethyl fragment (n=1) (AMDA, 1a) and a
phenylbutyl chain length (n=3) as found in compound
8
6
a and the classical tricyclic antidepressants.
with respect to N-alkylation, we explored a parallel
series of N-alkylated derivatives of AMDA (1a±1e), the
chain lengthened form of AMDA (6a±6c), and imipra-
mine (3a±3c) to test this hypothesis.
Several pharmacophore models for 5-HT2A receptors
have been proposed based on the SARs of known
4
,5
antagonists. Typically, the essential geometric char-
acteristics are described by the distances between two
N-Methylation of AMDA (Table 2) progressively
decreases anity. In contrast, mono- and dimethylation of
the imipramine-like compound 6a and of the imipramine
analogue 3a has little e€ect on anity.
Ê
aromatic rings (d =4.6±7.3 A) and the distances
between each aromatic ring and the basic amine nitro-
3
Ê
gen (d =5.2±8.4 A, d =5.7±8.5 A). The corresponding
Ê
1
2
dimensions for the minimum energy conformation of
AMDA (1a) are similar to existing agents with respect
While the number of di€erent alkylation patterns is
limited in this series, the results suggest that, at least
with respect to nitrogen substitution, the short and long
chain series bind di€erently. One possible explanation
for the di€erence between AMDA and 6 with respect to
Ê
to the aromatic rings (d =4.9 A) but deviate sub-
3
stantially in that it is not symmetrical with respect to the
Ê
Ê
two amine-ring distances (d =3.8 A, d =5.2 A), d
1
1
2
being much shorter than is considered optimal. The
distance parameters for compound 6a are quite similar
to those of classical antidepressants including cypro-
heptadine (2) and imipramine (3c). Thus, unlike AMDA
Table 2. The e€ect of chain length on 5-HT2A receptor anity and
molecular geometry
(1a), compound 6a is consistent with existing pharma-
cophores. Crystal structures of ¯exible tricyclic amines
like imipramine usually show an extended aminoalkyl
6
chain but folded conformers that more closely resemble
AMDA are energetically accessible. Molecular dynamics
Table 1. The e€ect of chain length on 5-HT2A receptor anity and
molecular geometry
Ê
a
(A)
Ê
(A)
a
Ê
(A)
a
K
i
(nM)b
Compound
n
d
1
d
2
d
3
K
i
(nM)a
6
4
0
1
2
3
3.7
3.7
4.9
12,000
20
R
1
R
2
Compound
1
3
1
5
6
a
3.8
5.2
6.0
5.2
6.2
7.6
4.9
4.9
4.9
480
32
H
H
H
CH
Ð
a
b
c
d
e
20
52
540
4000
721
32
13
22
Ð
Ð
392
160
140
Ð
a
CH
CH
Ð
3
Imipramine
Cyproheptadine
Ð
Ð
6.5
6.1
7.2
6.1
4.8
4.9
160
1.6
3
3
CH
2
Ph
H
Ð
a
Distances measured for chain extended conformers.
[
b 3
H]Ketanserin labeled cloned 5-HT2A sites. Values represent the
mean of computer-derived K estimates (using LIGAND) of quad-
ruplicate determinations. Standard errors typically range between 15
and 25% of the K value.
a 3
[
H]Ketanserin labeled, cloned 5-HT2A sites. Values represent the
estimates (using LIGAND) of quad-
ruplicate determinations. Standard errors typically range between 15
and 25% of the K value.
i
mean of computer-derived K
i
i
i

S. P. Runyon et al. / Bioorg. Med. Chem. Lett. 11 (2001) 655±658
657
N-alkylation is that, due to the proximity of the tricyclic
ring system and the steric bulk of the methyl groups,
dimethyl AMDA preferentially adopts a conformation
with a buried ammonium ion NH. While 6 can adopt a
folded conformation that places the nitrogen within a
region of space similar to that for AMDA, dimethylation
similarly buries the ammonium ion NH. The steric clash
of a folded dimethyl 6c can be relieved by adopting a
more chain extended and necessarily less AMDA-like
conformation.
ligand and stably transfected NIH3T3 cells expressing
1
1
the 5-HT2A receptor (GF-62 cells). Full details for
measurements of other receptors and transporters can
be found at the NIMH Psychoactive Drug Screening
Program web site (http://pdsp.cwru.edu/pdsp.htm).
Ligand Synthesis
9-Aminomethyl-9,10-dihydroanthracene (1a) was pre-
1
2
pared as previously described. 9-(N-Methylamino-
methyl)-9,10-dihydroanthracene (1b), 9-(N,N-dimethyl-
aminomethyl)-9,10-dihydroanthracene (1c), and 9-(N-
benzylaminomethyl)-9,10-dihydroanthracene (1e) were
Classical tricyclic amines such as imipramine bind with
high anity to several neurotransmitter receptors and
9
,10
transporters (e.g., 5-HT2A D , SERT, and NET).
2
ꢀ
Ligand SAR and ligand±receptor docking studies sug-
gest that the imipramine-related and AMDA-related
compounds interact with the 5-HT2A receptor di€er-
ently. This suggests that AMDA may behave di€erently
with respect to other neurotransmitter receptors and
binding sites. Table 3 shows the results of a preliminary
selectivity study. Given the high degree of receptor
sequence homology, it is not surprising that the AMDA
does not di€erentiate between 5-HT2A and 5-HT2C
sites. It is, however, quite remarkable that AMDA
shows at least 500-fold selectivity for 5-HT2A receptors
prepared by reduction (BH THF) of the amides
3
obtained by treatment of the acid chloride with methyl-,
dimethyl-, and benzylamine. The quaternary ammo-
nium bromide (1d) was obtained by treatment of 1c with
1
3
methyl bromide.
Imipramine (3c) and desmethyl imipramine (3b) were
purchased as the HCl salts. 5-(3-Aminopropyl)-(10,11)-
1
3
dihydro-5Hdibenz[b, f]azepine hydrochloride (3a) was
prepared by condensation of iminodibenzyl with 3-
chloropropionyl chloride followed by reduction of the
1
4
ꢀ
versus D receptors, and versus serotonin (SERT) and
2
norepinephrine (NET) transporters.
resulting amide with BH THF. The resulting 5-(3-
3
13
chloropropyl)-10,11-dihydro-5H-dibenz[b, f]azepine was
treated with potassium phthalimide in anhydrous DMF
and converted to the primary amine (3a) using NaBH4
5
1
3
The results suggest that AMDA and imipramine most
likely bind to the 5-HT2A receptor in di€erent fashions,
though the chain-lengthened aminoalkyl dihydro-
anthracene 6a may be more imipramine-like in binding
mode. While N-methylation decreases the 5-HT2A
receptor anity of AMDA, N-methylation increases the
anity in the imipramine and chain-lengthened AMDA
series. The fact that AMDA has a high degree of selec-
tivity and imipramine does not suggests that AMDA
1
in 2-propanol.
9-Amino-9,10-dihydroanthracene oxalate (4) was pre-
pared through a modi®ed Hofmann rearrangement of
1
9,10-dihydroanthracene-9-carboxamide using very mild
1
6
conditions. [Bis(tri¯uoroacetoxy)iodo]benzene in aqu-
eous acetonitrile conveniently converted 9,10-dihydro-
anthracene-9-carboxamide to 9-amino-9,10-dihydro-
anthracene (4) in 59% yield.
and imipramine bind to the D receptors, SERT, and
2
NET di€erently as well. Thus, AMDA behaves quite
di€erently from classical tricyclic amines and may be a
suitable template for the construction of structurally
9-(2-Aminoethyl)-9,10-dihydroanthracene oxalate (5)
was prepared by condensation of 9-anthraldehyde with
nitromethane in methylene chloride to provide trans-1-
novel, selective 5-HT receptor antagonists.
2
1
7
(
9-anthryl)-2-nitroethylene, which was reduced to
-(2-aminoethyl)anthracene using LAH/THF. The tar-
9
get molecule (5) was then prepared through reduction
Anity Determinations
1
8
using sodium metal in liquid ammonia.
Binding assays and data analysis were performed as
3
previously described using [ H]ketanserin as the radio-
9-(2-Aminopropyl)-9,10-dihydroanthracene oxalate (6a),
-[3-(N-methylaminopropyl)]-9,10-dihydroanthracene
9
oxalate (6b), and 9-[3-(N,N-dimethylaminopropyl]-9,10-
dihydroanthracene (6c) were prepared by the reduction
(BH THF) of the amides obtained by treatment of the
3
Table 3. Receptor and transporter selectivities of AMDA (1a) and
classical tricyclic agents
ꢀ
acid chloride of 9-(2-carboxyethyl)-9,10-dihydro-
1
K
i
(nM)
9
anthracene with ammonia gas, methylamine, and
dimethylamine, respectively.
a
b
c
SERTd
NETe
Comppound
5-HT2A 5-HT2C
D
2
AMDA (1a)
Imipramine (3c)
Cyproheptadine (2)
20
94
3
43
160
11
>10,000 >10,000 >10,000
726
112
5
4100
16
290
Acknowledgements
a 3
[
H]ketanserin.
b 3
H]mesulergine.
This work was supported by United States Public
Health Service Grant MH57969 (RBW), MH57635,
MH01366 (BLR), the NIMH Psychoactive Drug
Screening Program (BLR), and DA01642 (RAG).
[
c 3
[
H]spiperone.
d 3
H]paroxetine.
[
e 3
[
H]nisoxetine radioligands.

658
S. P. Runyon et al. / Bioorg. Med. Chem. Lett. 11 (2001) 655±658
Adapa, I. D.; Rodriguez, L.; Schwartz, R. W.; Haggart, D.;
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