Interactions of GR127935, a 5-HT(1B/D) receptor ligand, with functional 5-HT receptors.
GR127935 (N-[methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2 ,4-oxadiazol-3-yl) [1, 1-biphenyl]-4-carboxamide hydrochloride) has been recently introduced as an experimental tool to antagonize 5-HT(1B/D) receptor-mediated functional responses. The compound indeed exhibits a very high affinity and selectivity for 5-HT(1B/D) binding sites and it antagonizes a number of 5-HT(1B/D) receptor-mediated responses. The present experiments were performed to investigate the selectivity of GR127935 against functional responses mediated by 5-HT1-like, 'orphan' 5-HT1-like (5-ht7?), 5-HT2, 5-HT3 or 5-HT4 receptors in several in vivo preparations. Intravenous (i.v.) treatment with GR127935 (300 microg x kg(-1)) potently antagonized decreases in total carotid blood flow as well as hypotensive responses induced by the 5-HT1-like receptor agonist sumatriptan in rabbits. I.v. bolus injections of GR127935 (up to 500 and/or 1500 microg x kg(-1)) did not significantly modify 5-HT-induced: (i) tachycardia in the pig (5-HT4 receptor-mediated) and cat ('orphan' 5-HT1-like or, perhaps, 5-ht7 receptor-mediated); (ii) depressor effects in the rat and cat ('orphan' 5-HT1-like or 5-ht7 receptor-mediated); (iii) von Bezold-Jarisch reflex in the rat or the early phase of the urinary bladder contraction in the cat (both 5-HT3 receptor-mediated). In contrast, high doses (500-1500 microg x kg(-1)) of GR127935 suppressed 5-HT-induced pressor responses in the rat and cat and urinary bladder contractions (secondary phase) in the cat as well as the DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride)-induced pressor responses in the rat, which are all mediated by 5-HT2A receptors. In conclusion, the present study demonstrates that GR127935 is a selective 5-HT(1B/D) receptor antagonist devoid of interactions at 'orphan' 5-HT1-like (5-ht7?), 5-HT3 and 5-HT4 receptors. However, GR127935 possesses a moderate 5-HT2A receptor blocking property, which is consistent with its binding profile (pKi: 7.4). Lastly, in view of the potent antagonist action of GR127935, the sumatriptan-induced hypotension in rabbits seems to be mediated by 5-HT(1B/D) receptors.
De Vries
P
P
Department of Pharmacology, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, The Netherlands.
Apaydin
S
S
Villalón
C M
CM
Heiligers
J P
JP
Saxena
P R
PR
D000818:Animals; D002415:Cats; D004305:Dose-Response Relationship, Drug; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D018170:Sumatriptan / Q000494:pharmacology
D010069:Oxadiazoles; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C090701:GR 127935; D018170:Sumatriptan