De Los Angeles J E, Nikulin V I, Shams G, Konkar A A, Mehta R, Feller D R, Miller D D
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee-Memphis 38163, USA.
J Med Chem. 1996 Sep 13;39(19):3701-11. doi: 10.1021/jm960208o.
A series of trimetoquinol (1, TMQ) analogs were designed and synthesized based on the lead compound 2, a diiodinated analog of trimetoquinol which exhibits improved selectivity for beta 2-versus beta 1-adrenoceptors (AR). To determine the influence of 1-benzyl substituents of trimetoquinol on beta 2-AR binding affinity and selectivity, we replaced and/or removed the 3'-, 4'-, and 5'-methoxy substituents of trimetoquinol. Replacement of the 4'-methoxy group of 2 with an amino (21c) or acetamido (15) moiety did not significantly alter beta 2-AR and thromboxane A2/prostaglandin H2 (TP) receptor affinity. Substitution with a 4'-hydroxy (18) or -iodo (21b) group did not significantly alter beta 2-AR affinity, but greatly reduced TP receptor affinity (380- and 1200-fold, respectively). Further, the beta 2-AR can accommodate larger substituents such as a benzamide at the 4'-position (26b). Other monoiodo derivatives (24, 26a) have similar or slightly lower affinity to both beta 2-AR and TP receptor compared to their diiodo analogs. Interestingly, removal of the 4'-substituent of 3',5'-diiodo analogs increased beta 2-AR affinity with little or no effect on beta 1-AR and TP binding. Thus, analog 21a displayed highly potent (pKi 9.52) and selective (beta 2/beta 1 = 600) binding affinity for beta 2-AR. On the other hand, trifluoromethyl substituents at the 3'- and 5'-positions (27) essentially abolished binding affinity at beta 2-AR and TP receptors. The differential binding effects of the aforementioned trimetoquinol modifications on the receptor systems may reflect differences in the binding pocket that interacts with the benzyl portion of trimetoquinol analogs. Thus, manipulation of the 1-benzyl moiety of trimetoquinol (1) has resulted in analogs that exhibit potent beta 2-AR binding affinity and significantly lower beta 1-AR and TP receptor affinities.
基于先导化合物2（曲美托喹酚的二碘化类似物，对β2 - 肾上腺素能受体（AR）与β1 - 肾上腺素能受体的选择性有所提高）设计并合成了一系列曲美托喹酚（1，TMQ）类似物。为了确定曲美托喹酚的1 - 苄基取代基对β2 - AR结合亲和力和选择性的影响，我们取代和/或去除了曲美托喹酚的3' - 、4' - 和5' - 甲氧基取代基。用氨基（21c）或乙酰胺基（15）部分取代2的4' - 甲氧基基团，对β2 - AR和血栓素A2 / 前列腺素H2（TP）受体亲和力没有显著影响。用4' - 羟基（18）或 - 碘（21b）基团取代，对β2 - AR亲和力没有显著影响，但大大降低了TP受体亲和力（分别降低380倍和1200倍）。此外，β2 - AR在4' - 位可以容纳更大的取代基，如苯甲酰胺（26b）。与它们的二碘类似物相比，其他单碘衍生物（24，26a）对β2 - AR和TP受体具有相似或略低的亲和力。有趣的是，去除3'，5' - 二碘类似物的4' - 取代基增加了β2 - AR亲和力，对β1 - AR和TP结合几乎没有影响。因此，类似物21a对β2 - AR表现出高效（pKi 9.52）和选择性（β2 / β1 = 600）的结合亲和力。另一方面，3' - 和5' - 位的三氟甲基取代基（27）基本上消除了对β2 - AR和TP受体的结合亲和力。上述曲美托喹酚修饰对受体系统的不同结合效应可能反映了与曲美托喹酚类似物苄基部分相互作用的结合口袋的差异。因此，对曲美托喹酚（1）的1 - 苄基部分进行操作已得到了对β2 - AR具有高效结合亲和力且对β1 - AR和TP受体亲和力显著降低的类似物。
