Sazetidine-A is a potent and selective agonist at native and recombinant alpha 4 beta 2 nicotinic acetylcholine receptors

Sazetidine-A has been recently proposed to be a silent desensitizer of alpha 4 beta 2 nicotinic acetylcholine receptors (nAChRs), implying that it desensitizes alpha 4 beta 2 nAChRs without first activating them. This unusual pharmacological property of sazetidine-A makes it, potentially, an excellent research tool to distinguish between the role of activation and desensitization of alpha 4 beta 2 nAChRs in mediating the central nervous system effects of nicotine itself, as well as those of new nicotinic drugs. We were surprised to find that sazetidine-A potently and efficaciously stimulated nAChR-mediated dopamine release from rat striatal slices, which is mediated by alpha 4 beta 2* and alpha 6 beta 2* subtypes of nAChR. The agonist effects on native striatal nAChRs prompted us to re-examine the effects of sazetidine-A on recombinant alpha 4 beta 2 nAChRs in more detail. We expressed the two alternative stoichiometries of alpha 4 beta 2 nAChR in Xenopus laevis oocytes and investigated the agonist properties of sazetidine-A on both alpha 4(2)beta 2(3) and alpha 4(3)beta 2(2) nAChRs. We found that sazetidine-A potently activated both stoichiometries of alpha 4 beta 2 nAChR: it was a full agonist on alpha 4(2)beta 2(3) nAChRs, whereas it had an efficacy of only 6% on alpha 4(3)beta 2(2) nAChRs. In contrast to what has been published before, we therefore conclude that sazetidine-A is an agonist of native and recombinant alpha 4 beta 2 nAChRs but shows differential efficacy on alpha 4 beta 2 nAChRs subtypes.