Allosteric modulation of 5-HT3 serotonin receptors.
[(3)H]Granisetron binding to 5-HT(3) type serotonin receptors was examined in homogenates of rat forebrain and NG 108-15 cells. We have applied an allosteric model to 5-HT(3) receptor binding for the first time. Slope factors of displacement improved the modelling. Serotonin displaced [(3)H]granisetron binding with micromolar potency in forebrain and with nanomolar potency in NG 108-15 cells. Racemic and (+)verapamil, ifenprodil and GYKI-46903 were used as representative allosteric inhibitors of 5-HT(3) receptors. They displaced [(3)H]granisetron binding with great negative cooperativity (alpha>10) and exerted great negative cooperativity with serotonin binding (beta>10). Great negative cooperativity of these agents with serotonin and [(3)H]granisetron binding cannot be distinguished from dual competitive displacement. Trichloroethanol (data from literature) had no cooperativity with [(3)H]granisetron binding (alpha~1) and exhibit positive cooperativity with serotonin (beta<1) in displacement. The allosteric model can lead to a more quantitative method in vitro to develop allosteric agents for 5-HT(3) receptors.
Maksay
Gábor
G
Molecular Pharmacology Group, Institute for Biomolecular Chemistry, Chemical Research Centre, Hungarian Academy of Sciences, H-1525 Budapest, POB 17, Hungary. maksay@chemres.hu
Bíró
Tímea
T
Bugovics
Gyula
G
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000465:Algorithms; D000494:Allosteric Regulation; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D017829:Granisetron / Q000378:metabolism; D006822:Hybrid Cells; D007700:Kinetics; D008297:Male; D051379:Mice; D008954:Models, Biological; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry* / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology; D014316:Tritium; D014700:Verapamil / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D017829:Granisetron; D010880:Piperidines; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin; D018490:Serotonin Agents; D014316:Tritium; D014700:Verapamil; C010739:ifenprodil