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 μM CLO represented 64±6% of 10 μM 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.