Discovery and optimization of substituted piperidines as potent, selective, CNS-penetrant α4β2 nicotinic acetylcholine receptor potentiators

The discovery of a series of small molecule α4β2 nAChR potentiators is reported. The structure–activity relationship leads to potent compounds selective against nAChRs including α3β2 and α3β4 and optimized for CNS penetrance. Compounds increased currents through recombinant α4β2 nAChRs, yet did not compete for binding with the orthosteric ligand cytisine. High potency and efficacy on the rat channel combined with good PK properties will allow testing of the α4β2 potentiator mechanism in animal models of disease.