Shams G, Romstedt K J, Gerhardt M A, Harrold M W, Miller D D, Feller D R
Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus 43210.
Eur J Pharmacol. 1990 Aug 2;184(1):21-31. doi: 10.1016/0014-2999(90)90663-q.
The beta 1- and beta 2-adrenoceptor agonist and thromboxane A2 (TXA2) antagonist properties of trimetoquinol (TMQ, I) and 1-benzyl substituted TMQ analogues [3'-iodo-4',5'-dimethoxy TMQ, II; 3',5'-diiodo-4'-dimethoxy TMQ, III; 3',4'-dimethoxy-5'-nitro TMQ, IV; 3',4'-dimethoxy-5'-amino TMQ; V; and 3',4'-dimethoxy TMQ, VI] were studied in guinea pig atria (beta 1) and trachea (beta 2), and in rat thoracic aorta and human platelets, respectively. The rank order of agonist activities in beta 1- and beta 2-adrenoceptor tissues was IV greater than or equal to I greater than II greater than V greater than III greater than VI and I greater than II = IV = V greater than VI greater than III, respectively. An increase of beta 2/beta 1-selectivity (2- to 3-fold) was observed for analogues V and VI as compared to TMQ. The rank order of inhibitory potency against U46619-induced contraction of rat aorta and human platelet aggregation and secretion was the same (I = II = III greater than IV greater than V greater than VI). The results show that varying the substituents at the 3'- and 5'-positions of the trimethoxybenzyl group of TMQ produces compounds which give different profiles of biological activity for beta-adrenoceptor agonism versus TXA2 antagonism. Certain TMQ analogues, notably analogue V, showed a greater selectivity as beta 2-receptor agonists and TXA2 antagonists in vascular smooth muscle than the parent drug (TMQ), and the iodinated analogues (II and III) have promise as potential radioligands or photoaffinity probes for thromboxane A2 receptors.
研究了曲美喹诺（TMQ，I）及其1-苄基取代的TMQ类似物[3'-碘-4',5'-二甲氧基TMQ，II；3',5'-二碘-4'-二甲氧基TMQ，III；3',4'-二甲氧基-5'-硝基TMQ，IV；3',4'-二甲氧基-5'-氨基TMQ；V；以及3',4'-二甲氧基TMQ，VI]分别在豚鼠心房（β1）和气管（β2）、大鼠胸主动脉和人血小板中的β1和β2肾上腺素能受体激动剂以及血栓素A2（TXA2）拮抗剂特性。在β1和β2肾上腺素能受体组织中，激动剂活性的排序分别为IV≥I＞II＞V＞III＞VI以及I＞II = IV = V＞VI＞III。与TMQ相比，观察到类似物V和VI的β2/β1选择性增加了2至3倍。对U46619诱导的大鼠主动脉收缩以及人血小板聚集和分泌的抑制效力排序相同（I = II = III＞IV＞V＞VI）。结果表明，改变TMQ三甲氧基苄基3'-和5'-位的取代基会产生具有不同生物活性谱的化合物，这些化合物在β肾上腺素能受体激动作用与TXA2拮抗作用方面表现不同。某些TMQ类似物，尤其是类似物V，在血管平滑肌中作为β2受体激动剂和TXA2拮抗剂比母体药物（TMQ）表现出更高的选择性，并且碘化类似物（II和III）有望作为血栓素A2受体的潜在放射性配体或光亲和探针。
