Effect of trimetoquinol analogs for antagonism of endoperoxide/thromboxane A2-mediated responses in human platelets and rat aorta

A. Mukhopadhyay, S. S. Navran, H. M. Amin, S. A. Abdel-Aziz, J. Chang, D. J. Sober, Duane Miller, D. R. Feller

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Abstract

The pharmacological properties of a limited series of tetrahydroisoquinoline [trimetoquinol (TMQ)] analogs for inhibition of endoperoxide (U46619)-mediated responses in human platelets and rat aorta were examined. All analogs blocked U46619-induced aggregatory and secretory responses in platelets, and contraction of rat aorta in a concentration-dependent manner. R-(+)-TMQ was a competitive-type inhibitor of U46619-induced contractions of rat aorta. The relative inhibitory potency for TMQ analogs against U46619-induced effects was TMQ > N-methyl TMQ ≥ erythro-α-methyl TMQ > threo-α-methyl TMQ ≥ α-dimethyl TMQ. R-(+)-TMQ and the azoprostanoid analog (U51605) were potent antagonists of U46619 action in rat aorta with pA2 values of 5.97 and 5.70, respectively. Other experiments indicated that U511605 was a partial agonist and R-(+)-TMQ was an inhibitor of U5 1605-induced contractions of rat aorta (pK(B) = 5.94). R-(+)-TMQ also blocked prostaglandin E2-mediated responses in rat aorta (pA2 = 5.46) but was ineffective as an antagonist of prostaglandin F(2α) and LTD4 responses in dog iris sphincter and guinea-pig trachea or lung parenchyma, respectively. The data indicate that 1) the TMQ analogs were antagonists of endoperoxide/thromboxane A2-mediated responses in rat aorta and human platelets involving a similar mechanism of action and 2) stereochemical requirements of these TMQ analogs for activation of beta adrenoceptors and antagonism of endoperoxide/thromboxane A2-mediated responses are different. It is concluded that selectivity for these two pharmacological properties of TMQ can be achieved by appropriate stereochemical modification of the tetrahydroisoquinoline nucleus.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume232
Issue number1
StatePublished - Mar 13 1985
Externally publishedYes

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Tretoquinol
Thromboxane A2
Aorta
Blood Platelets
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Tetrahydroisoquinolines
Pharmacology
Leukotriene D4

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Mukhopadhyay, A., Navran, S. S., Amin, H. M., Abdel-Aziz, S. A., Chang, J., Sober, D. J., ... Feller, D. R. (1985). Effect of trimetoquinol analogs for antagonism of endoperoxide/thromboxane A2-mediated responses in human platelets and rat aorta. Journal of Pharmacology and Experimental Therapeutics, 232(1), 1-9.

Effect of trimetoquinol analogs for antagonism of endoperoxide/thromboxane A2-mediated responses in human platelets and rat aorta. / Mukhopadhyay, A.; Navran, S. S.; Amin, H. M.; Abdel-Aziz, S. A.; Chang, J.; Sober, D. J.; Miller, Duane; Feller, D. R.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 232, No. 1, 13.03.1985, p. 1-9.

Research output: Contribution to journalArticle

Mukhopadhyay, A. ; Navran, S. S. ; Amin, H. M. ; Abdel-Aziz, S. A. ; Chang, J. ; Sober, D. J. ; Miller, Duane ; Feller, D. R. / Effect of trimetoquinol analogs for antagonism of endoperoxide/thromboxane A2-mediated responses in human platelets and rat aorta. In: Journal of Pharmacology and Experimental Therapeutics. 1985 ; Vol. 232, No. 1. pp. 1-9.
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AU - Abdel-Aziz, S. A.

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AU - Sober, D. J.

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AU - Feller, D. R.

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