Interactions of GR127935, a 5-HT1B/D receptor ligand, with functional 5-HT receptors
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, cilt.355, sa.4, ss.423-430, 1997 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 355 Sayı: 4
- Basım Tarihi: 1997
- Dergi Adı: NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
- Sayfa Sayıları: ss.423-430
- Anahtar Kelimeler: DOI GR127935, 5-HT, 5-HT receptors, 5-HT1B receptor, 5-HT1B/D receptor antagonist, 5-HT1-like receptor, sumatriptan
- Dokuz Eylül Üniversitesi Adresli: Hayır
Özet
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-HT1/BD 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-ht(7)?), 5-HT2, 5-HT3 or 5-HT4 receptors in several in vivo preparations. Intravenous (i.v.) treatment with GR127935 (300 mu gxkg(-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 mu gxkg(-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-ht(7) receptor-mediated); (ii) depressor effects in the rat and cat ('orphan' 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 contraction in the cat (both 5-HT3 receptor-mediated). In contrast, high doses (500-1500 mu gxkg(-1)) of GR127935 suppressed 5-HT-induced presser 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 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 antagonist devoid of interactions at 'orphan' 5-HT1-like (5-ht(7)?), 5-HT3 and 5-HT4 receptors. However, GR127935 possesses a moderate 5-HT2A receptor blocking property, which is consistent with its binding profile (pK(i): 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.