Cardiovascular effects of SL65.0472, a 5-HT receptor antagonist.
In this study, we describe the cardiovascular effects of SL65.0472 (7-fluoro-2-oxo-4-[2-[4-(thieno[3,2-c] pyridin-4-yl) piperazin-l-yl] ethyl]-1, 2-dihydroquinoline-1-acetamide), a novel 5-hydroxytryptamine (5-HT) receptor antagonist developed for the treatment of cardiovascular disease, in several in vivo models. The haemodynamic profile of SL65.0472 was evaluated in anaesthetised dogs. Following i.v. bolus doses of 0.03 mg/kg i.v. and 0.3 mg/kg, no significant changes in cardiac output, contractility or rate, systemic and pulmonary pressures, regional blood flows and vascular resistances or electrocardiogram were noted. After 1 mg/kg i.v. SL65.0472 significantly reduced arterial blood pressure. In conscious spontaneously hypertensive rats administration of SL65.0472 0.5 mg/kg p.o. had no effect on mean arterial blood pressure or heart rate. Vasoconstriction produced by 5-HT results primarily from the stimulation of two receptor subtypes, 5-HT(1B) and 5-HT(2A) receptors. In anaesthetised dogs SL65.0472 antagonised sumatriptan-induced decreases in saphenous vein diameter (5-HT(1B)-receptor mediated) with an ID(50) of 10.1 microg/kg i.v. (95% c.l. 8.3-12.4). In anaesthetised pithed rats SL65.0472 inhibited 5-HT pressor responses (5HT(2A)-receptor mediated) with ID(50) values of 1.38 microg/kg i.v. (95% c.l. 1.15-1.64) and 31.1 microg/kg p.o. (95% c.l. 22.6-42.6). The duration of the 5-HT(2A)-receptor antagonist effect of SL65.0472 following oral administration was evaluated in conscious rats. SL65.0472 (0.1 mg/kg p.o.) markedly inhibited 5-HT pressor responses 1 and 6 h after administration. Therefore, in vivo, SL65.0472 potently antagonises vasoconstriction mediated by 5-HT(1B) and 5-HT(2A) receptors but has minimal direct haemodynamic effects.
O'Connor
S E
SE
Cardiovascular/Thrombosis Research Department, Sanofi-Synthélabo, 1 avenue Pierre Brossolette, 91385 Chilly-Mazarin Cedex, France. stephen-eric.o'connor@sanofi-synthelabo.com
Grosset
A
A
La Rochelle
C D
CD
Gautier
E
E
Bidouard
J P
JP
Robineau
P
P
Caille
D
D
Janiak
P
P
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology*; D018170:Sumatriptan / Q000494:pharmacology*; 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; D000959:Antihypertensive Agents; D010879:Piperazines; D011804:Quinolines; D044302:Receptor, Serotonin, 5-HT1B; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D014662:Vasoconstrictor Agents; D018170:Sumatriptan; D011224:Prazosin