Synthesis and structure -: Activity relationship studies of 3,6-diazabicyclo[3.2.0]heptanes as novel α4β2 nicotinic acetylcholine receptor selective Agonists

A series of novel, potent neuronal nicotinic acetylcholine receptor (nAChR) ligands derived from 3,6-diazabicyclo[3.2.0]heptane have been synthesized and evaluated for binding affinity and agonist activity at the alpha 4 beta 2 nAChR subtype. Structure- activity relationship studies of these novel nAChR ligands focused on substitution effects on the pyridine ring, as well as stereo- and regiochemical influences of the 3,6-diazabicyclo[3.2.0]heptane core. Small 5-substituents on the pyridine ring had a modest impact on the binding affinities and functional activities. 6-Bromo, 6-chloro, and 6-methyl substituents on the pyridine ring led to increased binding affinities and improved functional activities. Most of the 6-N-pyridinyl -substituted 3,6-diazabicyclo[3.2.0]heptanes are selective for the alpha A beta 2 nAChR subtype. Compounds (IR,5S)-25, (I R,5S)55, and (I R,5S)-56 were virtually inactive as agonists at the h alpha 3 beta 4 nAChR but retained potency and efficacy at the h alpha 4 beta 2 nAChR subtype. 3-N-Pyridinyl-substituted series demonstrated more complex SAR. (IR,5R)39, (1R,5R)-41, and (IR,5R)-42 were found to be much more potent at the h alpha 3 beta 4.nAChR subtype, whereas (IR,5R)-38 and (JR,5R)-40 were very selective at the h alpha 4 beta 2 nAChR subtype. The SAR studies of these novel ligands led to the discovery of several compounds with interesting in vitro pharmacological profiles.