Effects of SL 65.0472, a novel 5-HT receptor antagonist, on 5-HT receptor mediated vascular contraction.
5-hydroxytryptamine (5-HT) contracts vascular smooth muscle and pharmacological and molecular biological data suggest that these effects are mediated primarily by stimulation of 5-HT(1B) and 5-HT(2A) 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-HT(1B)-mediated contraction), SL 65.0472 antagonised sumatriptan-induced contractions in a competitive manner (pA(2) 8. 17+/-0.36). 5-HT contracts rabbit aorta by stimulation of 5-HT(2A) 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-HT(1B) and 5-HT(2A) receptors. SL 65.0472 produced rightward parallel shifts of the 5-HT concentration response curves in all tissues studied (pA(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.
Galzin
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AM
Cardiovascular/Thrombosis Research Department, Sanofi-Synthélabo, 1 Avenue Pierre Brossolette, 91385 Cedex, Chilly-Mazarin, France.
Delahaye
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M
Hoornaert
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McCort
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O'Connor
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D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004285:Dogs; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D008297:Male; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D044302:Receptor, Serotonin, 5-HT1B; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D012501:Saphenous Vein / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology*; D018170:Sumatriptan / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
C416534:7-fluoro-2-oxo-4-(2-(4-(thieno(3,2-c)pyridin-4-yl)piperazin-1-yl)ethyl)-1,2-dihydroquinoline-1-acetamide; D016166:Free Radical Scavengers; C470302:HTR1B protein, human; D010879:Piperazines; D011804:Quinolines; D044302:Receptor, Serotonin, 5-HT1B; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D014662:Vasoconstrictor Agents; D012701:Serotonin; D018170:Sumatriptan