Pharmacologic antagonism of thromboxane A2 receptors by trimetoquinol analogs in vitro and in vivo
- Ohio State University, Columbus (USA)
Although (-)-(S)-trimetoquinol (1-(3,4,5-trimethoxy-benzyl)- 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; TMQ) is recognized as a potent bronchodilator, (+)-(R)-TMQ is a selective antagonist of human platelet aggregation and serotonin secretion induced by thromboxane A2 (TXA2) agonists. To confirm the pharmacological actions of TMQ analogs, the interaction of the drugs with TXA2 receptors was examined in human platelets and in a mouse sudden death model. The inhibitory potencies of TMQ analogs (pIC50 values) for displacement of (3H)SQ 29,548 binding to platelets showed excellent correlation with the respective pIC50 (-log IC50) values for U46619-induced aggregation (r = 0.99, P less than 0.01) and serotonin secretion (r = 0.99, P less than 0.01) in human platelet-rich plasma and for whole blood aggregation (r = 0.99, P less than 0.01). In each system, the rank order of inhibitory potencies was rac-iodoTMQ greater than or equal to (+)-(R)-TMQ greater than rac-TMQ much greater than (-)-(S)-TMQ. Antithrombotic effects of TMQ analogs were evaluated in a mouse sudden death model. In vivo antithrombotic potencies of these compounds were consistent with the in vitro potencies as TXA2 receptor antagonists in platelet systems. Administration of rac-iodoTMQ, (+)-(R)-TMQ and rac-TMQ 15 min before the injection of U46619 (800 micrograms/kg, iv) protected mice against U46619-induced sudden death. On the other hand, (-)-(S)-TMQ did not protect animals against death. Protection of U46619-induced cardiopulmonary thrombosis by TMQ analogs was seen at doses of 3-100 mg/kg.
- OSTI ID:
- 5163242
- Journal Information:
- Chirality; (United States), Vol. 3:2; ISSN 0899-0042
- Country of Publication:
- United States
- Language:
- English
Similar Records
Binding of an ( sup 125 I) labelled thromboxane A2/prostaglandin H2 receptor agonist to baboon platelets
Inhibition of rabbit platelet activation in vitro by antagonists of platelet-activating factor (PAF)
Related Subjects
PROSTAGLANDINS
RECEPTORS
SEROTONIN
SECRETION
VASODILATORS
BIOLOGICAL EFFECTS
BIOCHEMICAL REACTION KINETICS
BLOOD COAGULATION
BLOOD PLATELETS
IN VITRO
IN VIVO
MAN
MICE
PHARMACOLOGY
THROMBOSIS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
AMINES
ANIMALS
AROMATICS
AUTONOMIC NERVOUS SYSTEM AGENTS
AZAARENES
AZOLES
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY FLUIDS
CARDIOVASCULAR AGENTS
CARDIOVASCULAR DISEASES
DISEASES
DRUGS
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
HYDROXY COMPOUNDS
INDOLES
ISOTOPE APPLICATIONS
KINETICS
MAMMALS
MATERIALS
MEMBRANE PROTEINS
NEUROREGULATORS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PRIMATES
PROTEINS
PYRROLES
RADIOPROTECTIVE SUBSTANCES
REACTION KINETICS
RODENTS
SYMPATHOMIMETICS
TRYPTAMINES
VASCULAR DISEASES
VERTEBRATES
550201* - Biochemistry- Tracer Techniques