Structure-activity studies and analgesic efficacy of N-(3-pyridinyl)-bridged bicyclic diamines, exceptionally potent agonists at nicotinic acetylcholine receptors.
A series of exceptionally potent agonists at neuronal nicotinic acetylcholine receptors (nAChRs) has been investigated. Several N-(3-pyridinyl) derivatives of bridged bicyclic diamines exhibit double-digit-picomolar binding affinities for the alpha 4 beta 2 subtype, placing them with epibatidine among the most potent nAChR ligands described to date. Structure-activity studies have revealed that substitutions, particularly hydrophilic groups in the pyridine 5-position, differentially modulate the agonist activity at ganglionic vs central nAChR subtypes, so that improved subtype selectivity can be demonstrated in vitro. Analgesic efficacy has been achieved across a broad range of pain states, including rodent models of acute thermal nociception, persistent pain, and neuropathic allodynia. Unfortunately, the hydrophilic pyridine substituents that were shown to enhance agonist selectivity for central nAChRs in vitro tend to limit CNS penetration in vivo, so that analgesic efficacy with an improved therapeutic window was not realized with those compounds.
Bunnelle
William H
WH
Neuroscience Research, Abbott Laboratories, Department R47W, Building AP9A, Abbott Park, Illinois 60064-6117, USA. william.h.bunnelle@abbott.com
Daanen
Jerome F
JF
Ryther
Keith B
KB
Schrimpf
Michael R
MR
Dart
Michael J
MJ
Gelain
Arianna
A
Meyer
Michael D
MD
Frost
Jennifer M
JM
Anderson
David J
DJ
Buckley
Michael
M
Curzon
Peter
P
Cao
Ying-Jun
YJ
Puttfarcken
Pamela
P
Searle
Xenia
X
Ji
Jianguo
J
Putman
C Brent
CB
Surowy
Carol
C
Toma
Lucio
L
Barlocco
Daniela
D
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D003959:Diamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D006572:Heterocyclic Compounds, Bridged-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D010147:Pain Measurement; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000700:Analgesics; D003959:Diamines; D006572:Heterocyclic Compounds, Bridged-Ring; D008024:Ligands; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D004298:Dopamine