Effects of SL 65.0472, a novel 5-HT receptor antagonist, on 5-HT receptor mediated vascular contraction

5-Hydroxytryptamine (5-MT) contracts vascular smooth muscle and pharmacological and molecular biological data suggest that these effects are mediated primarily by stimulation of 5-HT1B and 5-HT2A receptor subtypes. We have studied the properties of 7-fluoro-2-oxo-4-[2-[4-(thieno[3,2-c] pyridin-4-yl) piperazin-1-yl] ethyl]-1,2-dihydroquinoline-1-acetamide (SL 65.0472), a novel 5-HT receptor antagonist, in isolated vascular preparations contracted by 5-HT or sumatriptan. In canine isolated saphenous vein strips (putatively 5-HT1B-mediated contraction), SL 65.0472 antagonised sumatriptan-induced contractions in a competitive manner (p A(2) 8.17 +/- 0.36). 5-HT contracts rabbit aorta by stimulation of 5-HT2A receptors. SL 65.0472 displaced the 5-HT concentration response curve in rabbit aorta rightwards with a significant reduction in maximum. The apparent pK(B) value was 8.58 +/- 0.18. 5-HT-induced contractions of human coronary arteries are mediated by a mixed population of 5-HT1B and 5-HT2A receptors. SL 65.0472 produced rightward parallel shifts of the 5-HT concentration response curves in all tissues studied (p A(2) 8.8 +/- 0.14, n = 7). In conclusion, SL 65.0472 is a potent antagonist of vascular smooth muscle contraction in vitro mediated by 5-HT receptor stimulation. (C) 2000 Elsevier Science B.V. All rights reserved.