INTERACTIONS OF GR127935, A 5-HT1B D RECEPTOR-LIGAND, WITH FUNCTIONAL5-HT RECEPTORS/

GR127935 enyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1, 1-biph enyl]-4-carboxamide hydrochloride) has been recently introduced as an experimental tool to antagonize 5-HT1B/D receptor-mediated functional responses. The compound indeed exhibits a very high affinity and selec tivity for 5-HT1B/D binding sites and it antagonizes a number of 5-HT1 /BD receptor-mediated responses. The present experiments were performe d to investigate the selectivity of GR127935 against functional respon ses mediated by 5-HT1-like, 'orphan' 5-HT1-like (5-ht(7)?), 5-HT2, 5-H T3 or 5-HT4 receptors in several in vivo preparations. Intravenous (i. v.) treatment with GR127935 (300 mu gxkg(-1)) potently antagonized dec reases in total carotid blood flow as well as hypotensive responses in duced by the 5-HT1-like receptor agonist sumatriptan in rabbits. I.v. bolus injections of GR127935 (up to 500 and/or 1500 mu gxkg(-1)) did n ot significantly modify 5-HT-induced: (i) tachycardia in the pig (5-HT 4 receptor-mediated) and cat ('orphan' 5-HT1-like or, perhaps, 5-ht(7) receptor-mediated); (ii) depressor effects in the rat and cat ('orpha n' 5-HT1-like or 5-ht(7) receptor-mediated); (iii) von Bezold-Jarisch reflex in the rat or the early phase of the urinary bladder contractio n in the cat (both 5-HT3 receptor-mediated). In contrast, high doses ( 500-1500 mu gxkg(-1)) of GR127935 suppressed 5-HT-induced presser resp onses in the rat and cat and urinary bladder contractions (secondary p hase) in the cat as well as the DOI +/-)-1-(2,5-dimethoxy-4-iodophenyl )-2-aminopropane hydrochloride)-induced presser responses in the rat, which are all mediated by 5-HT2A receptors. In conclusion, the present study demonstrates that GR127935 is a selective 5-HT1/BD receptor ant agonist devoid of interactions at 'orphan' 5-HT1-like (5-ht(7)?), 5-HT 3 and 5-HT4 receptors. However, GR127935 possesses a moderate 5-HT2A r eceptor blocking property, which is consistent with its binding profil e (pK(i): 7.4). Lastly, in view of the potent antagonist action of GR1 27935, the sumatriptan-induced hypotension in rabbits seems to be medi ated by 5-HT1B/D receptors.