Iodinated analogs of trimetoquinol as highly potent and selective beta 2-adrenoceptor ligands

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.