Synthesis, nicotinic acetylcholine receptor binding affinities, and molecular modeling of constrained epibatidine analogues

Article abstract of DOI:10.1021/jm025613w

Conformationally constrained epibatidine analogues 20a,b and 23a,b were synthesized using a radical cyclization as the key step. Radioligand displacement assays to six defined rat nicotinic acetylcholine receptor (nAChR) subtypes showed that 20a,b bind with moderate affinities, while 23a,b have low affinities. 20a exhibits higher affinity for the β2 containing subtype than for the β4 containing counterpart, while 20b possesses reversed selectivity. Modeling studies suggest that the spatial distribution of the ligand's atoms around the pharmacophore elements may control their nAChR subtype selectivity.

Full text of DOI:10.1021/jm025613w

J . Med. Chem. 2003, 46, 921-924
921
Syn th esis, Nicotin ic Acetylch olin e
Recep tor Bin d in g Affin ities, a n d
Molecu la r Mod elin g of Con str a in ed
Ep iba tid in e An a logu es
Zhi-Liang Wei,† Pavel A. Petukhov,† Yingxian Xiao,‡
Werner Tu¨ckmantel,† Clifford George,§
F igu r e 1.
Sch em e 1a
Kenneth J . Kellar,‡ and Alan P. Kozikowski*,†
Drug Discovery Program, Department of Neurology,
Department of Pharmacology, Georgetown University
Medical Center, 3900 Reservoir Road, NW,
Washington, D.C. 20057, and Naval Research Laboratory,
4555 Overlook Avenue, SW, Washington, D.C. 20375
Received November 18, 2002
Ab st r a ct : Conformationally constrained epibatidine ana-
logues 20a ,b and 23a ,b were synthesized using a radical
cyclization as the key step. Radioligand displacement assays
to six defined rat nicotinic acetylcholine receptor (nAChR)
subtypes showed that 20a ,b bind with moderate affinities,
while 23a ,b have low affinities. 20a exhibits higher affinity
for the â2 containing subtype than for the â4 containing
counterpart, while 20b possesses reversed selectivity. Model-
ing studies suggest that the spatial distribution of the ligand’s
atoms around the pharmacophore elements may control their
nAChR subtype selectivity.
a
Reagents: (i) MeI, Ag2CO3, CHCl3, 71-93%; (ii) n-BuLi, THF,
then (CH2O)n, -78 °C to room temperature, 49-51%; (iii) Br2,
EtOH, 88-91%; (iv) TBSCl, imidazole, DMAP, DMF, 98%; (v)
n-BuLi, THF, then 15, -78 °C to room temperature, 80-86%; (vi)
MsCl, Et3N, DMAP, CH2Cl2, 84-87%; (vii) n-Bu4NF, THF, 100%;
(viii) PPh3, CBr4, CH2Cl2, 87-88%; (ix) n-Bu3SnH, AIBN, toluene,
reflux, 85-87%.
Neuronal nAChRs hold considerable promise as thera-
peutic targets for the treatment of disorders of the CNS
and peripheral nervous systems. Drugs aimed at nAChRs
have potential for the treatment of neurodegenerative
disorders, such as Alzheimer’s disease, Parkinson’s
disease, dyskinesias, Tourette’s syndrome, schizophre-
nia, attention deficit disorder, anxiety, and pain.1-3
nAChRs are ligand-gated ion channels and composed
of combinations of one or more R and â subunits, and
different subunit combinations define different receptor
subtypes with distinct biophysical, physiological, and
pharmacological properties, as well as different locations
within the nervous systems. Nine R and three â sub-
units have been cloned, which suggests the possibility
of a very large number of receptor subtypes. Although
we do not yet know all the rules of assembly, based on
studies of subunit mRNA and protein distribution
(measured with subunit-selective antibodies), five to
seven subtypes probably encompass the large majority
of the nAChRs in the CNS and peripheral nervous
systems. To further advance the field and to be able to
better understand the different roles the subtypes play
in normal physiology and pathology and to eventually
exploit these receptors as potential therapeutic targets,
it is important to better understand their pharmacology.
The novel alkaloid epibatidine (1), isolated from the
Ecuadorian poisonous frog Epipedobates tricolor,4 was
found to have powerful analgesic activity and high
binding affinity to nAChRs.5 Alhough its high toxicity
has limited its therapeutic potential, it nonetheless
provides an attractive lead structure for the design of
new ligands selective for distinct nAChR subtypes.5,6-12
Epibatidine has four low energy conformers with the
internitrogen (N+-N) distances ranging from 4.7 to 5.5
Å due to the presence of one rotatable bond connecting
the chloropyridine ring.13 It is uncertain which low
energy conformer of epibatidine is responsible for its
high affinity binding to nAChRs. The internitrogen
distance related to the pharmacophore of the ligand’s
supposed binding conformation is still under debate.13-19
Therefore, the synthesis and evaluation of conforma-
tionally restricted epibatidine analogues could help in
elucidating its “active” conformation on one hand and
in obtaining tools to study receptor subtype selectivity
on the other hand. We designed two types of conforma-
tionally constrained analogues of epibatidine, the spi-
rocycles 2 and fused cyclic structures 3 (Figure 1). We
present here our synthesis of 20a ,b and 23a ,b along
with their nAChR subtype binding affinities and mo-
lecular modeling.
As shown in Scheme 1, our synthesis started with the
commercially available 4a or 4b. Thus, O-alkylation of
4 afforded 5, which was deprotonated with n-BuLi at
-78 °C and quenched with paraformaldehyde to provide
the primary alcohol 6.20 Selective bromination of 6
followed by protection with tert-butyldimethylsilyl chlo-
ride gave 8. Treatment of the bromide 8 with n-BuLi at
-78 °C followed by addition of ketone 15, which could
be readily prepared from 1610 or 1721 (Scheme 2),
afforded the tertiary alcohol 9. Dehydration of alcohol
* To whom correspondence should be addressed. Tel: 202-687-0686.
Fax: 202-687-5065. E-mail: kozikowa@georgetown.edu.
† Drug Discovery Program, Department of Neurology, GUMC.
‡ Department of Pharmacology, GUMC.
§ Naval Research Laboratory.
10.1021/jm025613w CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/15/2003

922 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6
Letters
Sch em e 2a
summarized in Table 1. The two spirocyclic epibatidine
analogues 23a and 23b show relatively low binding
affinities to all receptor subtypes, probably due to the
orientation (endo) of the pyridine ring. In contrast, the
two fused cyclic analogues 20a and 20b have much
higher affinities (Ki values in nM range) for all of the
receptor subtypes, though they are still significantly
lower than those of epibatidine (1). It is interesting to
note that for each Râ subunit combination representing
a potential receptor subtype, 20a exhibits higher affinity
for the â2 containing subtype than for the â4 containing
counterpart. This pattern of higher affinity for â2
containing receptors is similar to most known nicotinic
ligands. In contrast, 20b possesses higher affinities for
the â4 containing subtype than for the â2 containing
counterpart. This is an unusual, if not unique, pattern
of selectivity among all nicotinic ligands that possess
moderate to high affinities for â2 and â4 containing
nicotinic receptor subtypes.
a
Reagents: (i) (a) B2H6, THF, then aq NaOH, 35% H2O2, 46%;
(b) Dess-Martin periodinane, CH2Cl2, 99%; (ii) SmI2 (2 equiv),
THF-MeOH, -78 °C to room temperature, 90%.
Sch em e 3a
To understand the moderate affinities of the ligands
20a and 20b and the low affinities of 23a and 23b, the
pharmacophore elements of 23a and 23b were compared
to those of 20a , 20b, and epibatidine (1), employing an
improved pharmacophore model that has been proposed
for the nAChR binding site.16,17 The ligands 20a , 20b,
23a , and 23b were subjected to conformational analysis
using the Advanced calculations module in Sybyl.24 It
was found that 20a and 20b have two stable conforma-
tions with a ∆E of less than 3 kcal/mol distinguished
by the conformation of the central six-membered ring
(twist 1: 20a 1 and 20b1, and twist 2: 20a 2 and 20b2).
There were no additional conformations found for 23a
and 23b since the other possible “envelop” conformation
of the central five-membered ring of 23a and 23b is
unstable due to an unfavorable interaction of H6 and
Hc (Table 2). The analysis of the RMS fit has shown that
the calculated conformations 20a 2, 20b1, 23a , and 23b
are almost identical to the X-ray structures of 13a , 20b,
21a , and 21b, respectively (RMS values < 0.14 Å).
a
Reagents: (i) (a) CF3CO2H, CH2Cl2; (b) (CF3CO)2O, pyridine,
CH2Cl2; (ii) POCl3, DMF, 0 °C to 95 °C, 59-65%; (iii) NaOMe,
MeOH, 85-96%.
9 with methanesulfonyl chloride gave the olefin 10.
Desilylation of 10 followed by treatment with PPh3/CBr4
furnished the bromide 12. Radical cyclization of 12
proceeded in both the 5-exo and the 6-endo fashion to
afford a 1.6:1 mixture of the spirocyclic product 14 and
the fused cyclic product 13 which demonstrates that the
primary radical attacked the olefin only from the exo
face (at both the 2- and 3-positions) of the 7-azabicyclo-
[2.2.1]hept-2-ene moiety.
The conversion of intermediates 13a and 13b to the
corresponding fused cyclic epibatidine analogues 20a
and 20b is outlined in Scheme 3. Removal of the Boc
group followed by reprotection as trifluoroacetamide
gave 18. Treatment of 18 under Vilsmeier conditions22
provided 19. The trifluoroacetyl protecting group was
finally removed under basic conditions to furnish the
fused epibatidine analogues 20. In the same manner,
the spirocyclic epibatidine analogues 23a and 23b were
synthesized from 14a and 14b, respectively (Scheme 3).
The stereochemistry of all constrained epibatidine
analogues, 20a , 20b, 23a , and 23b, was confirmed by
the X-ray crystallographic analysis of the interme-
diates 13a , 21a , and 21b, and of compound 20b itself.
Competition binding assays were carried out to
measure binding affinities (Ki values) of the four com-
pounds 20a , 20b, 23a , and 23b in their racemic forms
to six defined rat nicotinic receptor subtypes expressed
in stably transfected cell lines.23 Competition curves
were generated with 10 concentrations of the tested
compounds against a single concentration of (()-[3H]-
epibatidine. Ki values were determined by nonlinear
least squares regression analyses.23 The results are
Although several stable low energy conformations are
known for epibatidine (1), for our study we used only
one conformation that is believed to interact with
nAChRs (τ ) 7°).13 Two possible acceptor sites in the
binding site of the nAChR that are able to interact with
the charged hydrogen atoms Ha and Hb are marked as
AS1 and AS2 (Table 2).
A potential hydrogen donor site in the binding site
that is able to interact with the pyridine nitrogen is
marked as DS. The acceptors sites and donor site were
placed 2.9 Å from the corresponding atoms in 20a , 20b,
23a , and 23b (Table 2) using the defaults settings for
acceptor and donor sites in UNITY.24 The centroid of
the pyridine ring was defined as “c”. The pharmaco-
phore elements defined by Tønder et al.17 consist of the
distances between the acceptor and donor sites, the
distances between the acceptor sites and centroid c, and
the angle formed by centroid c and either one of the
acceptors sites AS1 or AS2, and the donor site DS. The
pharmacophore parameters obtained for epibatidine (1)
match the parameters reported by Tønder et al.17 In all
ligands the distance between the charged aliphatic
nitrogen and the pyridine nitrogen ranges between 4.9
and 5.9 Å, which is consistent with the observation that
the internitrogen distance (N+-N) in active nAChR

Letters
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6 923
Ta ble 1. Binding Affinities (Ki, nM) of (-)-Nicotine, (()-Epibatidine, and Four Constrained Epibatidine Analogues to Six nAChR
Subtypesa
ligand
R2â2
R2â4
R3â2
R3â4
R4â2
R4â4
nicotine
1
20a
20b
23a
23b
12 ( 2
0.025 ( 0.001
290 ( 5
112 ( 21
0.095 ( 0.017
717 ( 36
47 ( 11
0.035 ( 0.011
354 ( 10
443 ( 60
0.565 ( 0.121
2280 ( 220
201 ( 16
14900 ( 4500
13800 ( 1700
10 ( 2
40 ( 6
0.061 ( 0.009
73 ( 11
0.157 ( 0.006
637 ( 302
59 ( 7
32 ( 3
530 ( 81
295 ( 85
29200 ( 4300
6990 ( 2000
41 ( 14
10500 ( 4500
9460 ( 3700
12600 ( 5300
2690 ( 230
10700 ( 1000
7180 ( 190
19700 ( 4500
4070 ( 850
a
Kd values (nM) for [3H]-epibatidine used for calculating Ki values were 0.02 for R2â2, 0.08 for R2â4, 0.03 for R3â2, 0.30 for R3â4, 0.04
for R4â2, and 0.09 for R4â4 (Xiao and Kellar, 2003, manuscript in preparation). The Ki values of (-)-nicotine and epibatidine (1) shown
were the mean ( SEM of three to six independent measurements. The Ki values of 20a ,b and 23a ,b shown were the mean ( SEM of
three independent measurements.
Ta ble 2. Comparison of the Pharmacophore Fingerprints in Epibatidine (1) and Constrained Analogues of Epibatidine 20a ,b and
23a ,b. RMS Fit Values between 20a ,b and 23a ,b and the X-ray Structures of 13a , 20b, 21a , and 21b, Respectivelya
d (N+-N) d (AS1-DS) d (AS2-DS) d (AS1-c) d (AS2-c) ∆(c-AS1-DS) ∆(c-AS2-DS)
total
RMS fit
(Å)c
compound
(Å)
(Å)
(Å)
(Å)
(Å)
(deg)
(deg)
energyb
pharm modeld
4.5-6.0
4.7
4.9
5.0
4.4
5.1
5.9
5.9
7.3-8.0
6.5-7.4
30-36e
1f
4.6
6.6
6.3
4.0
5.6
7.8
9.1
8.7
8.4
9.9
3.7
3.0
3.6
2.9
3.6
6.7
6.7
7.0
6.4
6.9
6.4
6.9
7.5
7.5
64
33
42
77
52
16
30
34
26
30
31
23
23
23
32.4
31.7
32.7
31.1
32.0
38.1
38.0
20a 1
20a 2
20b1
20b2
23a
0.47
0.07
0.13
0.44
0.10
0.10
10.4
8.5
10.1
10.2
23b
a
Compounds 20a , 20b, 23a , and 23b are rendered in the conformations found in the X-ray structures of 13a , 20b, 21a , and 21b,
respectively. Total energy calculated using Tripos Force Field. c Pairwise RMS values between the heavy atoms of the calculated
b
conformers and the corresponding atoms in their X-ray structures. For compounds 20a , 23a , and 23b only matching atoms were used to
d
calculate the RMS values. The structures were aligned using the least-squares fit algorithm implemented in Sybyl. Tønder et al.17
e Rounded, the original values in ref 17 are 30.4° and 35.8°. f τ ( 2′-3′-1-2) is 4°, minimization by Tripos Force Field may be responsible
for the difference between our results and the results obtained by Tønder et al.17
F igu r e 2. (A) Alignment of epibatidine 1 (rendered as colored stick model) in a rectangular box measuring 10 × 8 × 7 Å3 (rendered
by violet lines). Carbon atoms are colored gray, hydrogen cyan, nitrogen blue, chlorine green. Acceptor site AS2, donor site DS,
centroid “c”, and center of mass CM are rendered by violet sticks. (B) Overlay of 1 rendered as yellow stick model, 20a 2 ren-
dered as green model, and 20b1 rendered as red model in the rectangular box. (C) Another projection of the models shown in the
panel B.
ligands should extend from 4.5 to 6.0 Å.16 Comparison
of the pharmacophore parameters derived from the two
conformations of ligands 20a and 20b reveals that
conformations 20a 2 and 20b1 exhibit the best match
with the pharmacophore model proposed by Tønder et
al. (Table 2).17 Moreover, none of the pharmacophore
parameters derived from acceptor site AS1 has a match
with the pharmacophore model. This may indicate that
only hydrogen Hb is required for binding, whereas the
hydrogen Ha is redundant and the position of Ha can
be used for further modification of the ligands 20a and
20b. Interestingly, the distance AS2-c and the angle
c-AS2-DS in conformers 20a 2 and 20b1 are within
the allowed range of 6.5-7.4 Å and 30-36°, whereas
the distance AS2-DS is 0.7 Å (in 20a 2) and 0.4 Å (in
20b1) larger than the maximum distance allowed by
the pharmacophore model.17 To determine how well
these ligands overlay with each other, both nitrogen
atoms, acceptor site AS2, and donor site DS of epibati-
dine (1), 20a 2, and 20b1 were aligned using the least-
squares fit algorithm implemented in Sybyl (Figure
2B,C). The pairwise RMS values are 0.44 Å for 1 and
20a 2, and 0.51 Å for 1 and 20b1. These deviations are
large enough to weaken the putative hydrogen bonds

924 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6
Letters
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or ionic interactions between these ligands and the
binding site, suggesting that the larger than 8.0 Å
distance AS2-DS may be responsible for the moderate
affinities of 20a and 20b in comparison to the affinities
of epibatidine (1). To compare the projections of ligands
1, 20a , and 20b to the space surrounding the pharma-
cophore elements, these ligands were enclosed in a
rectangular box measuring 10 × 8 × 7 Å3 (Figure 2B,C).
The box was split into eight equal smaller rectangular
boxes by planes dividing each side of the box into half.
Ligand 1 was placed inside the box so that the phar-
macophore elements AS2 and DS were located on the
bottom of the box and on the line dividing the box into
the Y1 and Y2 halves (sectors) simultaneously, whereas
the center of mass of ligand 1 and centroid c were
located in the plane dividing the box into sectors Y1 and
Y2 (Figure 2A). After that, the ligands 20a and 20b
were overlaid on ligand 1 as described above. As a
result, the aromatic rings of all ligands are located in
the sector X1 and the 7-azabicyclo[2.2.1]heptane moi-
eties of all ligands are located in the sector X2. Com-
parison of 1, 20a , and 20b shows that the 7-azabicyclo-
[2.2.1]heptane moiety of 20a projects into the sector Y1,
whereas this moiety in 20b is located mostly in the
sector Y2. Five out of seven heavy atoms of the pyridine
ring (carbons 4, 5, 6, nitrogen 3, and chlorine) in 20a
project into the sector Y2, whereas the same five atoms
in 20b project into the sector Y1. Interestingly, all atoms
of the middle ring of 20a are located in sector Z2,
whereas only two atoms in the middle ring of 20b are
located in sector Z2, the rest of them projecting into
sector Z1. Therefore, despite the good match among the
pharmacophore elements of epibatidine (1) and the
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optimum values determined by Tønder et al. (Table 2).17
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Ack n ow led gm en t. We thank Haizhu P. Wang and
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and ligand binding assays. This work was supported
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DA12976) and by the National Institute of Mental
Health through the Psychoactive Drug Screening Pro-
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