sq-29548 and 1-(2--4--5-trimethoxybenzyl)-6-7-dihydroxy-1-2-3-4-tetrahydroisoquinoline

Trimetoquinol (TMQ), a nonprostanoid compound, inhibits thromboxane A2 agonist-induced responses in platelets and vascular smooth muscle. Sixteen TMQ analogs were used to examine the stereochemical requirements of the interaction with thromboxane A2/prostaglandin H2 (TP) receptor sites in human platelets (HP), and cultured rat vascular endothelial (RVEC) and smooth muscle (RVSMC) cells. [3H]SQ 29548 was used as the ligand for TP receptors. The receptor binding affinities of these TMQ analogs for TP receptors in HP, RVEC and RVSMC were highly correlated with each other, and to their reported inhibitory potency values against U46619-induced HP aggregation and serotonin secretion, and contraction of rat aorta. TP receptor binding affinities of TMQ and 8-fluoro TMQ isomers were highly stereoselective (R-isomer > S-isomer), and only the 8-fluoro TMQ isomers gave qualitatively different functional responses in rat aorta. The affinity of TMQ for TP receptors was increased by addition of iodine and fluorine atoms at the 5- and 8-positions of the catechol ring or by replacement of the methoxy groups with iodine atoms on the 1-benzyl ring system. The results indicate that: 1) the stereochemical requirements of TMQ analogs for interaction with TP receptors in these cell systems are the same; 2) although TMQ analogs act as TP receptor antagonists, differences in functional responses by 8-fluoro TMQ isomers in platelets and aorta are not explained by their relative binding affinities to TP receptors; and 3) asymmetric halogenated TMQ analogs should be useful as affinity probes for further characterization of TP receptors.

Topics: Adrenergic beta-Agonists; Animals; Aorta, Thoracic; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Cells, Cultured; Endothelium, Vascular; Fatty Acids, Unsaturated; Humans; Hydrazines; Kinetics; Male; Models, Biological; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Structure-Activity Relationship; Tretoquinol; Tritium

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Death, Sudden; Disease Models, Animal; Fatty Acids, Unsaturated; Humans; Hydrazines; Male; Mice; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Receptors, Prostaglandin; Receptors, Thromboxane; Stereoisomerism; Thromboxane A2; Tretoquinol; Tritium

Thromboxane A2 (TXA2) is a bioactive metabolite of arachidonic acid which produces vascular smooth muscle contraction and blood platelet aggregation. The goal of this study is to establish whether there are age-dependent differences of vascular contractility to TXA2. Thoracic aorta of F-344 rats of age 4-6 months (young) and 22-23 months (old) were used as a model to examine responses to U46619 [(15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid; a TXA2 agonist] alone or in the presence of prostanoid (SQ 29,548) or nonprostanoid (trimetoquinol, TMQ) endoperoxide/TXA2 receptor antagonists. Maximal contractile responses (84 and 89% relative to KCl) and EC50 values (23 and 55 nmol/l, respectively) to U46619 were the same in aortic strips of young and old animals. Experimentally determined pA2 and pKB values for SQ 29,548 and TMQ as antagonists of U46619-mediated contraction were unchanged in aorta of young (9.09 and 5.83, respectively) and old (9.41 and 6.10, respectively) rats. We conclude that the reactivity and population of TXA2 receptors in rat vascular smooth muscle are unaffected by the aging process.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aging; Animals; Aorta, Thoracic; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Male; Muscle Contraction; Muscle, Smooth, Vascular; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred F344; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Tretoquinol