Thromboxane A₂ receptor antagonists

Overview of the Pharmacological Properties of Daltroban, a Thromboxane A2/Prostanoid‐Receptor Partial Agonist

“…Only traces of TP-receptor mRNA were detected in the brain (91,92). These observations were corroborated by functional studies showing that in the rat, TP receptor-mediated plasma albumin extravasation (7,143) occurred primarily in organs possessing the TxA,-synthesizing enzyme (32,157), the highest TP-receptor mRNA expression (91,92) and TP-receptor density (38,39).…”

“…The latter study showed evidence for a TP receptor-mediated membrane labilizing action of TxA, (15). Indeed, erythrocytes do not possess a high density of TP receptors (32,38,39,91,92,157), suggesting that TP-receptor reserve in erythrocytes is too low for daltroban to evoke a functional response. TP receptor-mediated erythrocyte lysis may be of importance in a variety of cardiovascular disease states such as myocardial and cerebral ischemia and circulatory shock.…”

“…produced significant bronchoconstriction in guinea pigs with peak changes in lung resistance and dynamic lung compliance of +74% and -23%, respectively. Sulotroban, under similar experimental conditions, was without any direct effect (38). TP-receptor reserve in guinea pig lungs in likely to be high (Table 1); thus, depending upon the degree of intrinsic activity at TP receptors, daltroban and possibly other purported TP-receptor antagonists (e.g., sulotroban) will exert partial-agonist activity at TP receptors within the pulmonary system (38,100).…”

“…In the coronary circulation, therefore, which possesses a relatively high TP-receptor reserve (32,38,39,91,92,157), daltroban exhibits intrinsic vasoconstrictor activity (100) (Tables 1, 2). In human platelets and bovine coronary artery and rat cultured vascular smooth muscle cells, daltroban appears to act as an agonist of moderate intrinsic activity and moderate potency at TP receptors (Table 2).…”

Terutroban et récepteurs TP endothéliaux dans l’athérogenèse

“…Les inhibiteurs de la thromboxane synthétase (TSI) (Figure 1) ont montré une activité assez décevante dans les études cliniques [8,9]. Quant aux premiers antagonistes sélectifs des récepteurs TP (Figure 1) décrits, ils appartenaient à une série d'acides 13-azaprostanoïques bloquant les actions pharmacologiques de l'U46619, un agoniste puissant et sélectif des récep-teurs TP [8]. Le premier antagoniste des récepteurs TP de structure non prostanoïde décrit a été le BM 13177, ou sulotroban ; plusieurs autres antagonistes ont été développés depuis, comme le daltroban, le ramatroban et le seratrodast.…”