title: Different pharmacological properties of two equipotent antagonists (clozapine and rauwolscine) for 5-HT2B receptors in rat stomach fundus.
abstract: On the basis of the previously demonstrated constitutive activity in natural systems and the possibility of specific ligand-induced conformations, the aims of this study were: (i) to characterize the effects of two competitive antagonists (rauwolscine, RAU and clozapine, CLO) with very similar potencies for 5-HT(2B) receptors in a natural system (rat stomach fundus), and (ii) to evaluate a new method for detecting ligand-specific generated conformations through the study of the effects of RAU and CLO in 5-HT efficacy and in the time course of the response to the agonists. RAU and CLO behaved as competitive antagonists and showed similar potencies (pA(2) 7.56+/-0.25 and 7.50+/-0.30, respectively). However, RAU displayed greater efficacy than CLO in relaxing basal tension (10 microM CLO represented 64+/-6% of 10 microM RAU-induced relaxation). CLO partially reverted RAU-induced relaxation and RAU promoted an additional relaxation of maximal CLO-induced relaxation. This may indicate different degrees of inverse agonism. RAU also was more effective in generating insurmountable antagonism after long-term incubation (>3 hr) and modified the time course of the 5-HT(2B) response to 5-HT; conversely, CLO did not affect the time course of this response. This suggests that classical competitive antagonists may generate different specific conformational states and differential effects on receptor system regulation.
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela, Avenida de las Ciencias s/n, Campus Sur, 15782 Santiago de Compostela, A Coruña, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Villazón
authors.forename: María José
authors.initials: MJ
authors.lastname: Enguix
authors.forename: Helena
authors.initials: H
authors.lastname: Tristán
authors.forename: María Angeles
authors.initials: MA
authors.lastname: Honrubia
authors.forename: José
authors.initials: J
authors.lastname: Brea
authors.forename: Saul
authors.initials: S
authors.lastname: Maayani
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Cadavid
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Loza
mesh_terms: D000818:Animals; D003024:Clozapine / Q000494:pharmacology*; D005748:Gastric Fundus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013997:Time Factors; D015016:Yohimbine / Q000494:pharmacology*
chemical_list: D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D015016:Yohimbine; D012701:Serotonin; D003024:Clozapine