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Isomeric‐Activity ratios of trimetoquinol enantiomers on β‐adrenergic receptor subtypes: Functional and biochemical studies
Author(s) -
Fraundorfer Paul F.,
Lezama Edwin J.,
SalazarBookaman M. Margarita,
Fertel Richard H.,
Miller Duane D.,
Feller Dennis R.
Publication year - 1994
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530060207
Subject(s) - chemistry , enantiomer , pindolol , chinese hamster ovary cell , stimulation , stereochemistry , agonist , receptor , intrinsic activity , guinea pig , medicine , endocrinology , biochemistry
Trimetoquinol [1‐(3′,4′,5′‐trimethoxybenzyl)‐6,7‐dihydroxy‐1,2,3,4‐tetrahydroisoquinoline, TMQ] exists as two enantiomers, and the (−)‐(S)‐isomer is a potent β‐adrenergic receptor (β‐AR) agonist. Experiments were conducted to examine the functional and biochemical potencies of the (S)‐ and (R)‐enantiomers of TMQ for interaction with β‐AR subtypes in tissues, membrane fractions, and cell systems. The isomeric‐activity ratios (IARs) of the TMQ isomers [(S)‐isomer ≫ (R)‐isomer] for stimulation of β 1 ‐ and β 2 ‐AR of guinea pig right atria and trachea were 224 and 1585, respectively; these IARs were similar to those observed on atypical β‐AR systems of rat distal colon (575), rat brown adipocytes (398), but differed from that of rat esophageal smooth muscle (2884) in the presence of pindolol. In the absence of pindolol, the potencies for the TMQ enantiomers were slightly increased; however, the IARs remained unchanged in rat distal colon, rat brown adipocytes, and rat esophageal smooth muscle. Similarly, radioligand binding studies demonstrated that the TMQ isomer β‐AR affinities were stereoselective for the (−)‐(S)‐isomer in membranes of guinea pig left ventricle (β 1 ) and lung (β 2 ) giving IARs of 115 and 389, respectively; and in E. coli expressing human β 1 ‐ and β 2 ‐AR giving IARs of 661 and 724, respectively. Corresponding IARs of receptor affinities and stimulation of cAMP accumulation in Chinese hamster ovary cells expressing human β 2 ‐AR and rat β 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 stereoselective agonist for each β‐AR subtype, that the isomers generally fail to differentiate between the β‐AR subtypes, and that, based upon differences in IAR within β 3 ‐AR containing systems, subtypes of atypical β (or β 3 )‐AR may exist in adipose tissue and smooth muscle. © 1994 Wiley‐Liss, Inc.