ISOMERIC-ACTIVITY RATIOS OF TRIMETOQUINOL ENANTIOMERS ON BETA-ADRENERGIC-RECEPTOR SUBTYPES - FUNCTIONAL AND BIOCHEMICAL-STUDIES

Trimetoquinol [1-(3',4',5'-trimethoxybenzyl)-6, 7-dihydroxy-1,2,3,4-te trahydroisoquinoline, TMQ] exists as two enantiomers, and the (-)-(S)- isomer is a potent p-adrenergic receptor (beta-AR) agonist. Experiment s were conducted to examine the functional and biochemical potencies o f the (S)- and (R)-enantiomers of TMQ for interaction with P-AR subtyp es in tissues, membrane fractions, and cell systems. The isomeric-acti vity ratios (IARs) of the TMQ isomers [(S)-isomer >> (R)-isomer] for s timulation of beta(1)- and beta(2)-AR of guinea pig right atria and tr achea were 224 and 1585, respectively; these IARs were similar to thos e observed on atypical beta-AR systems of rat distal colon (575), rat brown adipocytes (398), but differed from that of rat esophageal smoot h muscle (2884) in the presence of pindolol. In the absence of pindolo l, the potencies for the TMQ enantiomers were slightly increased; howe ver, the IARs remained unchanged in rat distal colon, rat brown adipoc ytes, and rat esophageal smooth muscle. Similarly, radioligand binding studies demonstrated that the TMQ isomer beta-AR affinities were ster eoselective for the (-)-(S)-isomer in membranes of guinea pig left ven tricle (beta(1)) and lung (beta(2)) giving IARs of 115 and 389, respec tively; and in E. coli expressing human beta(1)- and beta(2)-AR giving IARs of 661 and 724, respectively. Corresponding IARs of receptor aff inities and stimulation of cAMP accumulation in Chinese hamster ovary cells expressing human beta(2)-AR and rat beta(3)-AR were 331 and 282, and 118 and 4678, respectively. These results indicate that the (-)-( S)-isomer of TMQ exhibits high affinity, and is a potent and highly st ereoselective agonist for each beta-AR subtype; that the isomers gener ally fail to differentiate between the beta-AR subtypes, and that, bas ed upon differences in IAR within beta(3)-AR containing systems, subty pes of atypical beta (or beta(3))-AR may exist in adipose tissue and s mooth muscle. (C) 1994 Wiley-Liss, Inc.