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1.
Bioorg Med Chem ; 9(8): 2129-37, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11504649

ABSTRACT

Quinolin-2-ones bearing a heteroaryl-piperazine linked by a two carbon chain at the 3- or 4-position were synthesised and evaluated as mixed 5-HT(1B)/5-HT(2A) receptor antagonists. Potent mixed antagonists were obtained with thieno[3,2-c]pyridine derivatives. In this series, compound 2.1 (SL 65.0472) proved to be functional antagonist at both the 5-HT(2A) receptor (rat in vivo 5-HT-induced hypertension model) and the 5-HT(1B) receptor (dog in vitro saphenous vein assay).


Subject(s)
Piperazines/chemical synthesis , Quinolines/chemical synthesis , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Animals , Dogs , Piperazines/chemistry , Piperazines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Rats , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT2A , Receptors, Serotonin/drug effects , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology
2.
Eur J Pharmacol ; 404(3): 361-8, 2000 Sep 22.
Article in English | MEDLINE | ID: mdl-10996601

ABSTRACT

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.


Subject(s)
Aorta/drug effects , Coronary Vessels/drug effects , Piperazines/pharmacology , Quinolines/pharmacology , Saphenous Vein/drug effects , Serotonin Antagonists/pharmacology , Vasoconstriction/drug effects , Animals , Aorta/physiology , Coronary Vessels/physiology , Dogs , Female , Free Radical Scavengers/pharmacology , Humans , Male , Piperazines/chemistry , Quinolines/chemistry , Rabbits , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT2A , Receptors, Serotonin/drug effects , Receptors, Serotonin/physiology , Saphenous Vein/physiology , Serotonin/pharmacology , Serotonin Antagonists/chemistry , Sumatriptan/pharmacology , Vasoconstriction/physiology , Vasoconstrictor Agents/pharmacology
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