ISSN:
0899-0042
Keywords:
radioligand binding
;
SQ 29,548
;
thrombosis
;
U46619
;
whole blood
;
Chemistry
;
Organic Chemistry
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
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 〈 0.01) and serotonin secretion (r = 0.99, P 〈 0.01) in human platelet-rich plasma and for whole blood aggregation (r = 0.99, P 〈 0.01). In each system, the rank order of inhibitory potencies was rac-iodoTMQ ≥ (+)-(R)-TMQ 〉 rac-TMQ ≫ (-)-(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 μg/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. Our findings show that these TMQ analogs act as potent and highly stereospecific TXA2 receptor antagonists in vitro and in vivo.
Additional Material:
4 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/chir.530030206
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