title: Sazetidine-A is a potent and selective agonist at native and recombinant alpha 4 beta 2 nicotinic acetylcholine receptors.
abstract: Sazetidine-A has been recently proposed to be a "silent desensitizer" of alpha4beta2 nicotinic acetylcholine receptors (nAChRs), implying that it desensitizes alpha4beta2 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 alpha4beta2 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 alpha4beta2(*) and alpha6beta2(*) subtypes of nAChR. The agonist effects on native striatal nAChRs prompted us to re-examine the effects of sazetidine-A on recombinant alpha4beta2 nAChRs in more detail. We expressed the two alternative stoichiometries of alpha4beta2 nAChR in Xenopus laevis oocytes and investigated the agonist properties of sazetidine-A on both alpha4(2)beta2(3) and alpha4(3)beta2(2) nAChRs. We found that sazetidine-A potently activated both stoichiometries of alpha4beta2 nAChR: it was a full agonist on alpha4(2)beta2(3) nAChRs, whereas it had an efficacy of only 6% on alpha4(3)beta2(2) nAChRs. In contrast to what has been published before, we therefore conclude that sazetidine-A is an agonist of native and recombinant alpha4beta2 nAChRs but shows differential efficacy on alpha4beta2 nAChRs subtypes.
authors: Eli Lilly and Company, Lilly Research Centre, Sunninghill Road, Windlesham, Surrey, GU20 6PH, United Kingdom. zwart_ruud@lilly.com
authors: Ruud
authors: R
authors: Zwart
authors: Anna L
authors: AL
authors: Carbone
authors: Mirko
authors: M
authors: Moroni
authors: Isabel
authors: I
authors: Bermudez
authors: Adrian J
authors: AJ
authors: Mogg
authors: Elizabeth A
authors: EA
authors: Folly
authors: Lisa M
authors: LM
authors: Broad
authors: Andrew C
authors: AC
authors: Williams
authors: Deyi
authors: D
authors: Zhang
authors: Chunjin
authors: C
authors: Ding
authors: Beverly A
authors: BA
authors: Heinz
authors: Emanuele
authors: E
authors: Sher
mesh_terms: D000818:Animals; D001384:Azetidines / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D018722:Nicotinic Agonists / Q000378:metabolism* / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics* / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D001384:Azetidines; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; C403531:nicotinic receptor alpha4beta2; C514816:sazetidine-A