ISSN:
1432-1912
Keywords:
Key words DOI
;
GR127935
;
5-HT
;
5-HT receptors
;
5-HT1B receptor
;
5-HT1B/D receptor antagonist
;
5-HT1-like receptor
;
Sumatriptan
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/PL00004964
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