cinanserin and Thrombosis

Pathogenic thrombus formation accounts for the etiology of many serious conditions including myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. Despite the development of numerous anticoagulants and antiplatelet agents, the mortality rate associated with these diseases remains high. In recent years, however, significant epidemiological evidence and clinical models have emerged to suggest that modulation of the glycoprotein VI (GPVI) platelet receptor could be harnessed as a novel antiplatelet strategy. As such, many peptidic agents have been described in the past decade, while more recent efforts have focused on the development of small molecule modulators. Herein the rationale for targeting GPVI is summarized and the published GPVI modulators are reviewed, with particular focus on small molecules. A qualitative pharmacophore hypothesis for small molecule ligands at GPVI is also presented.

Topics: Binding Sites; Biological Products; Humans; Ligands; Losartan; Molecular Dynamics Simulation; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Protein Kinase Inhibitors; Signal Transduction; Small Molecule Libraries; Thrombosis

The relationship of serotonin to the inhibition of collateral blood flow was investigated. Five cats, in which the aorta contained a 6 microgram injection of serotonin in a closed aortic segment exhibited depressed hindlimb blood flow. The serotonin effects were eliminated in three animals by pretreatment with cinarserin HCl, a serotonin antagonist. The caudal 1.5 cm of the aorta was occluded in 24 cats by a blood clot formed by injection of thromboplastin subsequent to ligation. Eight of these animals were pretreated with cinanserin HCl and exhibited a significant improvement in hindlimb collateral blood flow. Serotonin was reduced in nine of these animals with reserpine/p-CPA treatment, and they exhibited the most significant recovery of all treated animals. Seven of the cats with blood serotonin reduced by decreasing blood platelets showed no improvement in hindlimb blood flow. The results of this study indicate that serotonin is a factor in the inhibition of collateral blood flow which follows arterial thrombosis.

Topics: Animals; Aorta, Abdominal; Aortic Diseases; Blood Cell Count; Blood Platelets; Cats; Cinanserin; Collateral Circulation; Disease Models, Animal; Fenclonine; Hindlimb; Premedication; Receptors, Serotonin; Reserpine; Serotonin; Thrombosis