Structure-Activity Studies and Analgesic Efficacy of N-(3-Pyridinyl)-Bridged Bicyclic Diamines, Exceptionally Potent Agonists at Nicotinic Acetylcholine Receptors
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- 作者：William H. Bunnelle ; Jerome F. Daanen ; Keith B. Ryther ; Michael R. Schrimpf ; Michael J. Dart ; Arianna Gelain ; Michael D. Meyer ; Jennifer M. Frost ; David J. Anderson ; Michael Buckley ; Peter Curzon ; Yi
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：July 26, 2007
- 年：2007
- 卷：50
- 期：15
- 页码：3627 - 3644
- 全文大小：256K
- 年卷期：v.50,no.15(July 26, 2007)
- ISSN：1520-4804
文摘
A series of exceptionally potent agonists at neuronal nicotinic acetylcholine receptors (nAChRs) has beeninvestigated. Several N-(3-pyridinyl) derivatives of bridged bicyclic diamines exhibit double-digit-picomolarbinding affinities for the 
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2 subtype, placing them with epibatidine among the most potent nAChR ligandsdescribed to date. Structure-activity studies have revealed that substitutions, particularly hydrophilic groupsin 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 achievedacross 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 enhanceagonist selectivity for central nAChRs in vitro tend to limit CNS penetration in vivo, so that analgesicefficacy with an improved therapeutic window was not realized with those compounds.
42 subtype, placing them with epibatidine among the most potent nAChR ligandsdescribed to date. Structure-activity studies have revealed that substitutions, particularly hydrophilic groupsin 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 achievedacross 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 enhanceagonist selectivity for central nAChRs in vitro tend to limit CNS penetration in vivo, so that analgesicefficacy with an improved therapeutic window was not realized with those compounds.