Interactions of GR127935, a 5-HT1B/D receptor ligand, with functional 5-HT receptors |
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Authors: | P De Vries S Apaydin Carlos M Villalón J P C Heiligers P R Saxena |
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Institution: | (1) Department of Pharmacology, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, P. O. Box 1738, 3000 DR Rotterdam, The Netherlands, NL;(2) Dokus Eylul Universitesi Tip Fakultesi, Farmakoloji Anabilim Dali 35340, Inciralti Izmir, Turkey, TR;(3) Sección de Terapéutica Experimental, Departamento de Farmacología y Toxicología, CINVESTAV, I.P.N., Apdo. Postal 22026, 14000 México D.F., México, XX |
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Abstract: | 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-HT1B/D receptor-mediated functional responses. The compound indeed exhibits a very high affinity and selectivity for 5-HT1B/D binding sites and it antagonizes a number of 5-HT1B/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 invivo preparations. Intravenous (i.v.) treatment with GR127935 (300μg?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 1500μg?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) vonBezold-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 (500-1500μg?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-HT1B/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-HT1B/D receptors. |
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Keywords: | DOI GR127935 5-HT 5-HT receptors 5-HT1B receptor 5-HT1B/D receptor antagonist 5-HT1-like receptor Sumatriptan |
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