A series o
f exceptionally potent agonists at neuronal nicotinic acetylcholine receptors (nAChRs) has beeninvestigated. Several
N-(3-pyridinyl) derivatives o
f bridged bicyclic diamines exhibit double-digit-picomolarbinding a
ffinities
for the
![](/images/gi<font color=)
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![](/images/gi<font color=)
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f" BORDER=0 ALIGN="middle">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, di
fferentially modulate the agonist activity at ganglionic vs central nAChR subtypes,so that improved subtype selectivity can be demonstrated
in vitro. Analgesic e
fficacy has been achievedacross a broad range o
f pain states, including rodent models o
f acute thermal nociception, persistent pain,and neuropathic allodynia. Un
fortunately, the hydrophilic pyridine substituents that were shown to enhanceagonist selectivity
for central nAChRs
in vitro tend to limit CNS penetration
in vivo, so that analgesice
fficacy with an improved therapeutic window was not realized with those compounds.