Received for publication January 9, 2008.
Revised March 19, 2008.
Accepted for publication March 24, 2008.

Sazetidine-A is a potent and selective agonist at native and recombinant 42 nicotinic acetylcholine receptors

Abstract

Sazetidine-A has been recently proposed to be a "silent desensitizer" of 42 nicotinic acetylcholine receptors (nAChRs), implying that it desensitizes 42 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 42 nAChRs in mediating the CNS effects of nicotine itself, as well as those of new nicotinic drugs. Surprisingly, we found that sazetidine-A potently and efficaciously stimulates nAChR-mediated dopamine release from rat striatal slices, which is mediated by 42* and 62* nAChRs. The agonist effects on native striatal nAChRs prompted us to re-examine the effects of sazetidine-A on recombinant 42 nAChRs in more detail. We expressed the two alternative stoichiometries of 42 nAChR in Xenopus oocytes and investigated the agonist properties of sazetidine-A on both 4(2)2(3) and 4(3)2(2) nAChRs. We found that sazetidine-A potently activated both stoichiometries of 42 nAChR: it was a full agonist on 4(2)2(3) nAChRs, whereas it had an efficacy of only 6% on 4(3)2(2) nAChRs. In contrast to what has been published before, we therefore conclude that sazetidine-A is an agonist of native and recombinant 42 nAChRs while showing differential efficacy on 42 nAChRs subtypes.

Key words: Nicotinic cholinergic, Func. analysis receptor/ion channel mutants, Receptor binding studies