title: Structure-activity studies and analgesic efficacy of N-(3-pyridinyl)-bridged bicyclic diamines, exceptionally potent agonists at nicotinic acetylcholine receptors.
abstract: 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.
authors.affiliation: Neuroscience Research, Abbott Laboratories, Department R47W, Building AP9A, Abbott Park, Illinois 60064-6117, USA. william.h.bunnelle@abbott.com
authors.forename: William H
authors.initials: WH
authors.lastname: Bunnelle
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Daanen
authors.forename: Keith B
authors.initials: KB
authors.lastname: Ryther
authors.forename: Michael R
authors.initials: MR
authors.lastname: Schrimpf
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dart
authors.forename: Arianna
authors.initials: A
authors.lastname: Gelain
authors.forename: Michael D
authors.initials: MD
authors.lastname: Meyer
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Frost
authors.forename: David J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: Michael
authors.initials: M
authors.lastname: Buckley
authors.forename: Peter
authors.initials: P
authors.lastname: Curzon
authors.forename: Ying-Jun
authors.initials: YJ
authors.lastname: Cao
authors.forename: Pamela
authors.initials: P
authors.lastname: Puttfarcken
authors.forename: Xenia
authors.initials: X
authors.lastname: Searle
authors.forename: Jianguo
authors.initials: J
authors.lastname: Ji
authors.forename: C Brent
authors.initials: CB
authors.lastname: Putman
authors.forename: Carol
authors.initials: C
authors.lastname: Surowy
authors.forename: Lucio
authors.initials: L
authors.lastname: Toma
authors.forename: Daniela
authors.initials: D
authors.lastname: Barlocco
mesh_terms: 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
chemical_list: D000700:Analgesics; D003959:Diamines; D006572:Heterocyclic Compounds, Bridged-Ring; D008024:Ligands; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D004298:Dopamine