Cardiovascular effects of SL65.0472, a 5-HT receptor antagonist

• Published in: European journal of pharmacology 2001-03, Vol.414 (2), p.259-269
• Main Authors: O'Connor, Stephen E, Grosset, Alain, Drieu La Rochelle, Christophe, Gautier, Etienne, Bidouard, Jean-Pierre, Robineau, Pascale, Caille, Dominique, Janiak, Philip
• Format: Article
• Language: English
• Subjects: 5-HT 1B receptors; 5-HT 2A receptors; Animals; Antihypertensive agents; Antihypertensive Agents - pharmacology; Biological and medical sciences; Blood Pressure - drug effects; Blood Pressure - physiology; Cardiovascular system; Dogs; Haemodynamics; Heart Rate - drug effects; Heart Rate - physiology; Hemodynamics - drug effects; Hemodynamics - physiology; Male; Medical sciences; Pharmacology. Drug treatments; Piperazines - pharmacology; Prazosin - pharmacology; Quinolines - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin - drug effects; Receptors, Serotonin - physiology; Receptors, Serotonin, 5-HT1; Serotonin Antagonists - pharmacology; SL 65.0472; Sumatriptan - pharmacology; Vasoconstrictor Agents - pharmacology
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(01)00804-4

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 μg/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 μg/kg i.v. (95% c.l. 1.15–1.64) and 31.1 μg/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.