TY - JOUR T1 - Sazetidine-A Is a Potent and Selective Agonist at Native and Recombinant α4β2 Nicotinic Acetylcholine Receptors JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1838 LP - 1843 DO - 10.1124/mol.108.045104 VL - 73 IS - 6 AU - Ruud Zwart AU - Anna L. Carbone AU - Mirko Moroni AU - Isabel Bermudez AU - Adrian J. Mogg AU - Elizabeth A. Folly AU - Lisa M. Broad AU - Andrew C. Williams AU - Deyi Zhang AU - Chunjin Ding AU - Beverly A. Heinz AU - Emanuele Sher Y1 - 2008/06/01 UR - http://molpharm.aspetjournals.org/content/73/6/1838.abstract N2 - Sazetidine-A has been recently proposed to be a “silent desensitizer” of α4β2 nicotinic acetylcholine receptors (nAChRs), implying that it desensitizes α4β2 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 α4β2 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 α4β2* and α6β2* subtypes of nAChR. The agonist effects on native striatal nAChRs prompted us to re-examine the effects of sazetidine-A on recombinant α4β2 nAChRs in more detail. We expressed the two alternative stoichiometries of α4β2 nAChR in Xenopus laevis oocytes and investigated the agonist properties of sazetidine-A on both α4(2)β2(3) and α4(3)β2(2) nAChRs. We found that sazetidine-A potently activated both stoichiometries of α4β2 nAChR: it was a full agonist on α4(2)β2(3) nAChRs, whereas it had an efficacy of only 6% on α4(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 α4β2 nAChRs but shows differential efficacy on α4β2 nAChRs subtypes. The American Society for Pharmacology and Experimental Therapeutics ER -