412 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4
Holladay et al.
(17) Abbreviations are as defined in J . Org. Chem. 1996, 61, 22A,
unless otherwise noted.
ability to elicit changes in blood pressure and heart rate over
a 5-min data collection period.
(18) Pabreza, L. A.; Dhawan, S.; Kellar, K. J . [3H]Cytisine Binding
to Nicotinic Cholinergic Receptors in Brain. Mol. Pharmacol.
1990, 39, 9-12.
Ack n ow led gm en t. The authors thank Dr. Michael
Dart for helpful comments on the manuscript and
William Arnold for large-scale preparation of several key
intermediates.
(19) McBride, P. E. The Health Consequences of Smoking. Med. Clin.
N. Am. 1992, 76, 333-353.
(20) Carlson, G. M.; Ruddon, R. W.; Hug, C. C., J r.; Schmiege, S. K.;
Bass, P. Analysis of the Site of Nicotine Action on Gastric Antral
and Duodenal Contractile Activity. J . Pharmacol. Exp. Ther.
1970, 173, 377-383.
(21) Lukas, R. J . Expression of Ganglia-Type Nicotinic Acetylcholine
Receptors and Nicotinic Binding Sites by Cells of the IMR-32
Human Neuroblastoma Clonal Line. J . Pharmacol. Exp. Ther.
1993, 265, 294-302.
(22) Gopalakrishnan, M.; Monteggia, L. M.; Anderson, D. J .; Molinari,
E. J .; Piattoni-Kaplan, M.; Donnelly-Roberts, D.; Arneric, S. P.;
Sullivan, J . P. Stable Expression, Pharmacologic Properties and
Regulation of the Human Neuronal Nicotinic R4â2 Receptor. J .
Pharmacol. Exp. Ther. 1996, 276, 289-297.
(23) Luther, M. A.; Schoepfer, R.; Whiting, P.; Casey, B.; Blatt, Y.;
Montal, M. S.; Montal, M.; Lindstrom, J . A Muscle Acetylcholine
Receptor is Expressed in the Human Cerebellar Medulloblas-
toma Cell Line TE671. J . Neurosci. 1989, 9, 1082-1095.
(24) Lippiello, P. M.; Sears, S. B.; Fernandes, K. G. Kinetics and
Mechanism of L-[3H]nicotine Binding to Putative High Affinity
Receptor Sites in Rat Brain. Mol. Pharmacol. 1987, 31, 392-
400.
Refer en ces
(1) Spande, T. F.; Garaffo, H. M.; Edwards, M. W.; Yeh, H. J . C.;
Pannell, L.; Daly, J . W. Epibatidine: A Novel (Chloropyridyl)-
azabicycloheptane with Potent Analgesic Activity from an Ec-
uadoran Poison Frog. J . Am. Chem. Soc. 1992, 114, 3475-3478.
(2) Qian, C.; Li, T.; Shen, T. Y.; Libertine-Garahan, L.; Eckman, J .;
Biftu, T.; Ip, S. Epibatidine Is a Nicotinic Analgesic. Eur. J .
Pharmacol. 1993, 250, R13-R14.
(3) Badio, B.; Daly, J . W. Epibatidine, a Potent Analgetic and
Nicotinic Agonist. Mol. Pharmacol. 1994, 45, 563-569.
(4) Sullivan, J . P.; Bannon, A. W. Epibatidine: Pharmacological
Properties of a Novel Nicotinic Acetycholine Receptor Agonist
and Analgesic Agent. CNS Drug Rev. 1996, 2, 21-39.
(5) Khan, I. M.; Youngblood, K. L.; Printz, M. P.; Yaksh, T. L.;
Taylor, P. Spinal Nicotinic Receptor Expression in Spontane-
ously Hypertensive Rats. Hypertension 1996, 28, 1093-1099.
(6) Khan, I. M.; Marsala, M.; Printz, M. P.; Taylor, P.; Yaksh, T. L.
Intrathecal Nicotinic Agonist-Elicited Release of Excitatory
Amino Acids as Measured by In Vivo Spinal Microdialysis in
Rats. J . Pharmacol. Exp. Ther. 1996, 278, 97-106.
(7) Sullivan, J . P.; Decker, M. W.; Brioni, J . D.; Donnelly-Roberts,
D.; Anderson, D. J .; Bannon, A. W.; Kang, C.-H.; Adams, P.;
Piattoni-Kaplan, M.; Buckley, M.; Gopalakrishnan, M.; Williams,
M.; Arneric, S. P. (()-Epibatidine Elicits a Diversity of In Vitro
and In Vivo Effects Mediated by Nicotinic Acetylcholine Recep-
tors. J . Pharmacol. Exp. Ther. 1994, 271, 624-631.
(8) Bonhaus, D. W.; Bley, K. R.; Broka, C. A.; Fontana, D. J .; Leung,
E.; Lewis, R.; Shieh, A.; Wong, E. H. F. Characterization of the
Electrophysiological, Biochemical and Behavioral Actions of
Epibatidine. J . Pharmacol. Exp. Ther. 1995, 273, 1199-1203.
(9) Rao, T. S.; Correa, L. D.; Reid, R. T.; Lloyd, G. K. Evaluation of
Anti-nociceptive Effects of Neuronal Nicotinic Acetylcholine
Receptor (NAChR) Ligands in the Rat Tail-Flick Assay. Neu-
ropharmacology 1996, 35, 393-405.
(10) Holladay, M. W.; Lebold, S. A.; Lin, N.-H. Structure-Activity
Relationships of Nicotinic Acetylcholine Receptor Agonists as
Potential Treatments for Dementia. Drug Dev. Res. 1995, 35,
191-213.
(11) Sullivan, J . P.; Briggs, C. A.; Donnelly-Roberts, D.; Brioni, J .
D.; Radek, R. J .; McKenna, D. G.; Campbell, J . E.; Arneric, S.
P.; Decker, M. W.; Bannon, A. W. (()-Epibatidine Can Differ-
entially Evoke Responses Mediated by Putative Subtypes of
Nicotinic Acetylcholine Receptors (nAChRs). Med. Chem. Res.
1994, 4, 502-516.
(12) Badio, B.; Shi, D.; Garraffo, M.; Daly, J . W. Antinociceptive
Effects of the Alkaloid Epibatidine: Further Studies on Involve-
ment of Nicotinic Receptors. Drug Dev. Res. 1995, 36, 46-59.
(13) Khan, I. M.; Taylor, P.; Yaksh, T. L. Stimulatory Pathways and
Sites of Action of Intrathecally Administered Nicotinic Agents.
J . Pharmacol. Exp. Ther. 1994, 27, 1550-1557.
(14) Abreo, M. A.; Lin, N.-H.; Garvey, D. S.; Gunn, D. E.; Hettinger,
A.-M.; Wasicak, J . T.; Pavlik, P. A.; Martin, Y. C.; Donnelly-
Roberts, D. L.; Anderson, D. J .; Sullivan, J . P.; Williams, M.;
Arneric, S. P.; Holladay, M. W. Novel 3-Pyridyl Ethers With
Subnanomolar Affinity for Central Neuronal Nicotinic Acetyl-
choline Receptors. J . Med. Chem. 1996, 39, 817-825.
(15) Sullivan, J . P.; Donnelly-Roberts, D.; Briggs, C. A.; Anderson,
D. J .; Gopalakrishnan, M.; Piattoni-Kaplan, M.; Campbell, J .
E.; McKenna, D. G.; Molinari, E.; Hettinger, A.-M.; Garvey, D.
S.; Wasicak, J . T.; Holladay, M. W.; Williams, M.; Arneric, S. P.
A-85380 [3-(2(S)-Azetidinylmethoxy)Pyridine]: In Vitro Phar-
macological Properties of a Novel, High Affinity R4â2 Nicotinic
Acetylcholine Receptor Ligand. Neuropharmacology 1996, 35,
725-734.
(16) Effenberger, F.; Krebs, A.; Willrett, P. Zum Mechanismus der
Carbodesilylierung 4-bzw. 5-substituierter 2-(Trimethylsilyl)-
pyridine mit Benzaldehyd. (On the Mechanism of Carbodesily-
lation of 4- and 5-Substituted 2-(Trimethylsilyl)-pyridine with
Benzaldehyde.) Chem. Ber. 1992, 125, 1131-1140.
(25) Bannon, A. W.; Decker, M. W.; Holladay, M. W.; Curzon, P.;
Donnelly-Roberts, D.; Puttfarcken, P. S.; Bitner, R. S.; Diaz, A.;
Dickenson, A. H.; Porsolt, R. D.; Williams, M.; Arneric, S. P.
Broad-Spectrum Non-Opioid Analgesic Activity of Selective
Modulation of Neuronal Nicotinic Acetylcholine Receptors. Sci-
ence 1998, 279, 77-81.
(26) Donnelly-Roberts, D. L.; Puttfarcken, P. S.; Kuntzweiler, T. A.;
Briggs, C. A.; Anderson, D. J .; Campbell, J . E.; Piattoni-Kaplan,
M.; McKenna, D. G.; Wasicak, J . T.; Holladay, M. H.; Williams,
M.; Arneric, S. P. ABT-594. I. In Vitro Profile of a Novel
Analgesic Neuronal Nicotinic Acetylcholine Receptor (nAChR)
Ligand. J . Pharmacol. Exp. Ther. 1998, in press.
(27) Bannon, A. W.; Decker, M. W.; Curzon, P.; Buckley, M. J .; Kim,
D. J . B.; Lynch, J . K.; Wasicak, J . T.; Arnold, W. H.; Holladay,
M. W.; Arneric, S. P. 5-((2R)-Azetidinylmethoxy)-2-chloropyridine
[ABT-594]: A Novel, Orally Effective Antinociceptive Agent
Acting via Nicotinic Acetylcholine Receptors. II. In Vivo Char-
acterization. J . Pharmacol. Exp. Ther. 1998, in press.
(28) Decker, M. W.; Bannon, A. W.; Buckley, M. J .; Kim, D. J . B.;
Holladay, M. W.; Ryther, K. B.; Lin, N.-H.; Wasicak, J . T.;
Williams, M.; Arneric, S. P. Antinociceptive Effects of the Novel
Neuronal Nicotinic Acetylcholine Receptor Agonist, ABT-594, in
Mice. Eur. J . Pharmacol. 1998, in press.
(29) Lin, N.-H.; Gunn, D. E.; Ryther, K. B.; Garvey, D. S.; Donnelly-
Roberts, D. L.; Decker, M. W.; Brioni, J . D.; Buckley, M. J .;
Rodrigues, A. D.; Marsh, K. G.; Anderson, D. J .; Buccafusco, J .
J .; Pendergast, M. A.; Sullivan, J . P.; Williams, M.; Arneric, S.
P.; Holladay, M. W. Structure-Activity Studies on ABT-089: An
Orally Bioavailable 3-Pyridyl Ether Nicotinic Acetylcholine
Receptor (nAChR) Ligand with Cognition Enhancing Properties.
J . Med. Chem. 1997, 40, 385-390.
(30) Sullivan, J . P.; Donnelly-Roberts, D.; Briggs, C. A.; Gopalakrish-
nan, M.; Hu, I.; Campbell, J . E.; Anderson, D. J .; Piattoni-
Kaplan, M.; Molinari, E.; McKenna, D. G.; Gunn, D. E.; Lin, N.-
H.; Ryther, K. B.; He, Y.; Holladay, M. W.; Williams, M.; Arneric,
S. P. ABT-089 [2-Methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine
dihydrochloride]: A Potent and Selective Cholinergic Channel
Modulator with Cytoprotective Properties. J . Pharmacol. Exp.
Ther. 1997, 283, 235-246.
(31) Briggs, C. A.; McKenna, D. G.; Piattoni-Kaplan, M. Human R7
Nicotinic Acetylcholine Receptor Responses to Novel Ligands.
Neuropharmacology 1995, 34, 583-590.
J M9706224