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Sazetidine-A Is a Potent and Selective Agonist at Native and Recombinant 4β2 Nicotinic Acetylcholine Receptors

Eli Lilly & Company, Lilly Research Centre, Windlesham, Surrey, United Kingdom (R.Z., A.J.M., E.A.F., L.M.B., A.C.W., E.S.); Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana (D.Z., C.D., B.A.H.); and School of Life Sciences, Oxford Brookes University, Oxford, United Kingdom (A.L.C., M.M., I.B.).

Sazetidine-A has been recently proposed to be a "silent desensitizer" of 4β2 nicotinic acetylcholine receptors (nAChRs), implying that it desensitizes 4β2 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 4β2 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 4β2^* and 6β2^* subtypes of nAChR. The agonist effects on native striatal nAChRs prompted us to re-examine the effects of sazetidine-A on recombinant 4β2 nAChRs in more detail. We expressed the two alternative stoichiometries of 4β2 nAChR in Xenopus laevis oocytes and investigated the agonist properties of sazetidine-A on both 4(2)β2(3) and 4(3)β2(2) nAChRs. We found that sazetidine-A potently activated both stoichiometries of 4β2 nAChR: it was a full agonist on 4(2)β2(3) nAChRs, whereas it had an efficacy of only 6% on 4(3)β2(2) nAChRs. In contrast to what has been published before, we therefore conclude that sazetidine-A is an agonist of native and recombinant 4β2 nAChRs but shows differential efficacy on 4β2 nAChRs subtypes.

Address correspondence to: Dr. Ruud Zwart, Eli Lilly and Company, Lilly Research Centre, Sunninghill Road, Windlesham, Surrey, GU20 6PH, United Kingdom. E-mail: zwart_ruud{at}lilly.com