2076
A. Mazurov et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2073–2077
Table 5. Amides
adjustment of functional activity and desensitization to
optional levels.11
H
N
R4
In summary, highly potent and selective ligands for the
a7 subtype have been obtained by modification of 2-
(pyridylmethyl)quinuclidine. Three key pharmacophoric
elements have been identified: a basic nitrogen, a hydro-
gen-bond-accepting moiety and second polar region in-
volved in interaction with the receptor via H-bonding.
Electrophysiological data substantiate the therapeutic
potential of amide (+)-8l.
O
N
R1
Compounds R1
R4
a7 Affinity
Ki (nM)
8a
8b
8c
8d
8e
Pyridin-3-yl 4-Bromophenyl
Pyridin-3-yl 3-Bromophenyl
Pyridin-3-yl Phenyl
7
64
52
12
Pyridin-3-yl 4-Fluorophenyl
Pyridin-3-yl 4-(Dimethylamino)-
phenyl
134
Acknowledgements
8f
8g
8h
8i
Pyridin-3-yl 4-(Phenylthio)phenyl
Pyridin-3-yl 1-Methylpyrrol-2-yl
Pyridin-3-yl Thien-3-yl
9
155
790
0.4
Authors are indebted to Professor R. L. Papke (Univer-
sity of Florida) for in vitro functional characterization
of selected compounds.
Pyridin-3-yl 5-Bromothien-2-yl
Pyridin-3-yl 5-(Pyridin-2-yl)-
thien-2-yl
8j
0.7
References and notes
8k
8l
Pyridin-3-yl 5-Iodothien-2-yl
Pyridin-3-yl Benzo[b]furan-2-yl
Pyridin-3-yl Indol-3-yl
0.12 0.03
1
8
1. Bencherif, M.; Schmitt, J. D. Curr. Drug Targets—CNS
Neurological Disord. 2002, 1, 349; Schmitt, J. D. Curr.
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Pharmacol. Exp. Ther. 2004, 309, 16; Toma, L.; Barlocco,
D.; Gelain, A. Exp. Opin. Ther. Pat. 2004, 14, 1029;
Bunnelle, W. H.; Dart, M. J.; Schrimpf, M. R. Curr.
Topics Med. Chem. 2004, 4, 299.
8m
8n
8o
8p
8q
8r
Pyridin-3-yl 1-Methylindol-3-yl
Pyridin-3-yl 1-Hydroxynapht-2-yl
Pyridin-3-yl Styryl
521
1
0.6
5
Pyridin-3-yl a-Methylstyryl
Pyridin-3-yl b-Methylstyryl
87
Table 6. Sulfonamides
2. Bencherif, M.; Lovette, M. E.; Fowler, K. W.; Arrington,
S.; Reeves, L.; Caldwell, W. S.; Lippiello, P. M. J.
Pharmacol. Exp. Ther. 1996, 279, 1413; Bencherif, M.;
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Pharmacol. 2000, 409, 45; Papke, R. L.; Webster, J. C.;
Lippiello, P. M.; Bencherif, M.; Francic, M. M. J.
Neurochem. 2000, 75, 204; Gatto, G.; Bohme, G. A.;
Caldwell, W. S.; Letchworth, S. R.; Traina, V. M.; Obinu,
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A. A.; Miller, C. H. Abstract of Papers, 228th National
Meeting of the American Chemical Society, Philadelphia,
PA; American Chemical Society: Washington, DC, 2004;
Abstract 11.
O
S
H
N
R5
O
N
R1
Compounds
R1
R5
a7 Affinity
Ki (nM)
9a
9b
9c
9d
9e
Pyridin-3-yl
Pyridin-3-yl
Pyridin-3-yl
Pyridin-3-yl
Pyridin-3-yl
4-Bromophenyl
Phenyl
8088
418
4-Methoxyphenyl
4-Acetamidophenyl
Benzyl
8919
146
8839
3. Van Kampen, M.; Selbach, K.; Schneider, R.; Schiegel, E.;
Boess, F.; Schreiber, R. Psychopharmacology 2004, 172,
375.
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which creates a special challenge for the pharmacologi-
cal characterization of this receptor.9 Potency and
intrinsic activity values for carbamate (+)-5s
(EC50 = 300 nM; Imax = 0.19) and amide (+)-8l
(EC50 = 33 nM; Imax = 1.0) were determined by measur-
ing current activation in Xenopus oocytes expressing rat
nicotinic receptors. While carbamate (+)-5s is a partial
agonist, amide (+)-8l is a potent full agonist for the a7
receptor, which significantly exceeds the potency of the
known full agonist AR-R17779.10 Higher concentra-
tions of (+)-8l are required to produce residual inhibi-
tion (desensitization) than are required to activate the
receptor. Since the ratio of IC50 to EC50 is approxi-
mately 6, an optimal dose might be found to exhibit in
vivo efficacy of the a7 nicotinic full agonist. The nature
of substituents in positions 2 and 3 of the described
quinuclidine derivatives has an effect on the degree
of both activation and desensitization of the receptor.
Variation of diverse structural fragments allows the