Antiplatelet and antithrombotic activity of SL65.0472, a mixed 5-HT1B/5-HT2A receptor antagonist.
The antiplatelet and antithrombotic activity of SL65.0472 (7-fluoro-2-oxo-4-[2-[4-(thieno [3,2-c]pyrin-4-yl) piperazin-1-yl]ethyl]-1,2-di-hydroquinoline-acetamide), a mixed 5-HT1B/5-HT2A receptor antagonist was investigated on 5HT-induced human platelet activation in vitro, and in rat, rabbit and canine platelet dependent thrombosis models. SL65.0472 inhibited 5-HT-induced platelet shape change in the presence of EDTA (IC50 values = 35, 69 and 225 nM in rabbit, rat and human platelet rich plasma (PRP)), and also inhibited aggregation induced in human PRP by 3-5 microM 5-HT + threshold concentrations of ADP (0.5-1 microM) or collagen (0.3 microg/ml) with mean IC50 values of 49 +/- 13 and 48 +/- 6 nM respectively. SL65.0472 inhibited thrombus formation when given both intravenously 5 min and orally 2 h prior to assembly of an arterio-venous (A-V) shunt in rats as from 0.1 and 0.3 mg/kg respectively. It was active in a rabbit A-V shunt model with significant decreases in thrombus weight as from 0.1 mg/kg i. v. and at 10 mg/kg p.o. The delay to occlusion in an electric current-induced rabbit femoral artery thrombosis model was increased by 251% (p <0.05) after 20 mg/kg p.o. SL65.0472 (30 microg/kg i.v.) virtually abolished coronary cyclic flow variations (7.2 +/- 1.0/h to 0.6 +/- 0.6/h, p <0.05) and increased minimum coronary blood flow (1.2 +/- 0.8 ml/min to 31.8 +/- 8.4 ml/min, p <0.05) in a coronary artery thrombosis model in the anaesthetised dog. Finally, SL65.0472 significantly increased the amount of blood lost after rat tail transection at 3 mg/kg p.o. Thus the anti-5-HT2A component of SL65.0472 is reflected by its ability to inhibit 5-HT-induced platelet activation, and platelet-rich thrombus formation.
Berry
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CN
Cardiovascular/Thrombosis Department, Sanofi-Synthélabo, Chilly Mazarin, France. christopher.berry@sanofi-synthelabo.com
Lorrain
J
J
Lochot
S
S
Delahaye
M
M
Lalé
A
A
Savi
P
P
Lechaire
I
I
Ferrari
P
P
Bernat
A
A
Schaeffer
P
P
Janiak
P
P
Duval
N
N
Grosset
A
A
Herbert
J M
JM
O'Connor
S E
SE
D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D044302:Receptor, Serotonin, 5-HT1B; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D013927:Thrombosis / Q000188:drug therapy* / Q000517:prevention & control
C416534:7-fluoro-2-oxo-4-(2-(4-(thieno(3,2-c)pyridin-4-yl)piperazin-1-yl)ethyl)-1,2-dihydroquinoline-1-acetamide; D005343:Fibrinolytic Agents; C470302:HTR1B protein, human; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011804:Quinolines; D044302:Receptor, Serotonin, 5-HT1B; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists