Novel Acetylcholine and Carbamoylcholine Analogues: Development of a Functionally Selective α4β2 Nicotinic Acetylcholine Receptor Agonist

A series of carbamoylcholine and acetylcholine analogues were synthesized and characterized pharmacologically at neuronal nicotinic acetylcholine receptors (nAChRs). Several of the compounds displayed low nanomolar binding affinities to the alpha(4)beta(2) nAChR and pronounced selectivity for this subtype over alpha(3)beta(4), alpha(4)beta(4), and alpha(7) nAChRs. The high nAChR activity of carbamoylcholine analogue 5d was found to reside in its R-enantiomer, a characteristic most likely true for all other compounds in the series. Interestingly, the pronounced alpha(4)beta(2) selectivities exhibited by some of the compounds in the binding assays translated into functional selectivity. Compound 5a was a fairly potent partial alpha(4)beta(2) nAChR agonist with negligible activities at the alpha(3)beta(4) and alpha(7) subtypes, thus being one of the few truly functionally selective alpha(4)beta(2) nAChR agonists published to date. Ligand-protein docking experiments using homology models of the amino-terminal domains of alpha(4)beta(2) and alpha(3)beta(4) nAChRs identified residues Val 111(beta(2))/Ile 113(beta(4)), Phe 119(beta(2))/Gln 121(beta(4)), and Thr155(alpha(4))/Ser 150(alpha(3)) as possible key determinants of the alpha(4)beta(2)/alpha(3)beta(4)-selectivity displayed by the analogues. 4