Peter W. Sprague

9α-homo-9,11-epoxy-5,13-prostadienoic acid analogues: Specific stable agonist (SQ 26,538) and antagonist (SQ 26,536) of the human platelet thromboxane receptor

A newly synthesized 9 alpha-homo-9,11-epoxy-5,13-prostadienoic acid analogue, SQ 26, 536, (8(R)9(S)11(R)12(S)-9 alpha-homo-9,11-epoxy-5(Z), 13(E)-15S-hydroxyprostadienoic acid) inhibited arachidonic acid (AA)-induced platelet aggregation with an I50 value of 1.7 microM. SQ 26,536 did not inhibit prostaglandin (PG) synthetase activity of bovine seminal vesicle microsomes or thromboxane (Tx) synthetase activity of lysed human blood platelets. SQ 26,536 also inhibited platelet aggregation induced by epinephrine (secondary phase), 9,11-azoPGH2 and collagen but did not inhibit the primary phase of epinephrine-induced aggregation or ADP-induced platelet aggregation. SQ 26,538 (8(R)9(S)11(R)12(S)-9 alpha-homo-9,11-epoxy-5(Z),13(E)-15R-hydroxyprostadienoic acid), a 15-epimer of SQ 26,536, induced platelet aggregation with an A50 value of 2.5 microM. SQ 26,536 competitively inhibited SQ 26,538-induced platelet aggregation with a Ki value of 3 microM. Neither indomethacin, a PG synthetase inhibitor, nor SQ 80,338 (1-(3-phenyl-2-propenyl)-1H-imidazole), a Tx synthetase inhibitor, inhibited SQ 26,538- or 9,11-azoPGH2-induced platelet aggregation. These data indicate that SQ 26,536 and SQ 26,538 are stable antagonist and agonist, respectively, of the human blood platelet thromboxane receptor.

Chapter 7. Antihypertensive Agents

Publisher Summary Currently, it is not possible to prevent essential hypertension and this presents a challenge to the clinician, pharmacologist, and medicinal chemist to discover adequate therapies. This chapter discusses the beneficial effects of drug therapy in the management of hypertension, the significance of catecholamine levels in hypertension, role of the sympathoadrenal axis in hypertension, and the need for intact vascular endothelium for vascular responses to a number of agents. A cautionary note offered that the levels in mixed venous blood are unreliable indicators of sympathetic neural activity in hypertension. Current evidence supports the hypothesis that converting enzyme (CEI) exerts their hypotensive effects primarily by inhibition of circulating and tissue-bound converting enzyme. A summary of the pharmacology of enalapril (MK-421) has appeared along with an account of the clinical studies done with lisinopril (MK-521) that suggest this drug will be suitable for once-a-day anti-hypertensive therapy. Analogs of enalapril that have appeared include the perhydroindole derivative. New evidence suggests certain calcium entry blockers (CEB) affect neural regulation of blood vessels at several sites. Studies in anesthetized dogs indicate that nifedipine increases and verapamil decreases the sensitivity of carotidsinus baroreceptors apparently by interference with a calcium-dependent and a sodium-dependent mechanism, respectively. New studies have examined the interaction of various CEB with α-adrenoceptors and their effect on the processes mediated by a-adrenoceptors. The (+) and (-) antipodes of verapamil, nicardipine, and (+) D-600 showed similar inhibition of radioligand binding to al-adrenoceptors, whereas diltiazem and nifedipine showed a very low level of activity.