Different pharmacological properties of two equipotent antagonists (clozapine and rauwolscine) for 5-HT2B receptors in rat stomach fundus.
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.
Villazón
María
M
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.
Enguix
María José
MJ
Tristán
Helena
H
Honrubia
María Angeles
MA
Brea
José
J
Maayani
Saul
S
Cadavid
María Isabel
MI
Loza
María Isabel
MI
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*
D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D015016:Yohimbine; D012701:Serotonin; D003024:Clozapine