Iodinated Analogs of Trimetoquinol as Highly Potent and Selective β₂-Adrenoceptor Ligands

Abstract

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.

Synthesis of Oxacycles Employing the Oxa‐Pictet–Spengler Reaction: Recent Developments and New Prospects

“…Iodination of 312 with benzyltrimethylammonium dichloroiodate exclusively afforded the required o-iodoaniline 313. [233] Reaction of the latter with the TES-protected alkyne 314 gave 72 % of TES-tryptophol 315 as the sole product. [234] An analogous sequence, employing Larock indole synthesis, was recently reported by Zheng and coworkers [68] in which a TES-tryptophol was prepared, the silicon group directing the subsequent oxa-Pictet-Spengler cyclization.…”

2-Amino-4-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridines: Novel Selective β3-Adrenoceptor Agonists

“…Trimetoquinol (TMQ, 7 ; Chart ) is a known potent, nonselective β-AR agonist, used clinically in Japan as a bronchorelaxant. − Our laboratory has focused on TMQ structural modifications in order to obtain selective β-AR agonists. Our previous structural modifications of TMQ have generated potent, selective β 2 -AR agonists . In this study, we report novel structural modifications of TMQ, with the goal of synthesizing potent and selective β 3 -AR agonists.…”

“…Our previous structural modifications of TMQ have generated potent, selective β 2 -AR agonists. 22 In this study, we report novel structural modifications of TMQ, with the goal of synthesizing potent and selective β 3 -AR agonists. It has been discovered that the catechol moiety of TMQ is indispensable for the agonist activities at both human β 1 -and β 2 -AR, 23 whereas its degree of contribution to TMQ's β 3 -AR activity has not been evaluated.…”

Simple, Efficient and Controllable Synthesis of Iodo/Di-iodoarenes via Ipsoiododecarboxylation/Consecutive Iodination Strategy

“…Aryl iodides are among the most important organic compounds prevalent in biologically active compounds and organic synthetic intermediates123456. These iodides are particularly used in metalation processes78, nucleophilic substitutions910, and metal-catalyzed cross-coupling reactions111213 given the high reactivity of C–I.…”