Isomeric‐Activity ratios of trimetoquinol enantiomers on β‐adrenergic receptor subtypes: Functional and biochemical studies

Paul F. Fraundorfer, Edwin J. Lezama, M. Margarita Salazar‐Bookaman, Richard H. Fertel, Duane Miller, Dennis R. Feller

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Abstract

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 β1‐ and β2‐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 (β1) and lung (β2) giving IARs of 115 and 389, respectively; and in E. coli expressing human β1‐ and β2‐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 β2‐AR and rat β3‐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 β3‐AR containing systems, subtypes of atypical β (or β3)‐AR may exist in adipose tissue and smooth muscle. © 1994 Wiley‐Liss, Inc.

Original languageEnglish (US)
Pages (from-to)76-85
Number of pages10
JournalChirality
Volume6
Issue number2
DOIs
StatePublished - Jan 1 1994

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Tretoquinol
Enantiomers
Isomers
Adrenergic Receptors
Rats
Brown Adipocytes
Smooth Muscle
Pindolol
Adrenergic Agonists
Muscle
Guinea Pigs
Colon
Tissue
Membranes
Cricetulus
Trachea
Heart Atria
Heart Ventricles
Adipose Tissue
Ovary

All Science Journal Classification (ASJC) codes

  • Analytical Chemistry
  • Catalysis
  • Pharmacology
  • Drug Discovery
  • Spectroscopy
  • Organic Chemistry

Cite this

Isomeric‐Activity ratios of trimetoquinol enantiomers on β‐adrenergic receptor subtypes : Functional and biochemical studies. / Fraundorfer, Paul F.; Lezama, Edwin J.; Salazar‐Bookaman, M. Margarita; Fertel, Richard H.; Miller, Duane; Feller, Dennis R.

In: Chirality, Vol. 6, No. 2, 01.01.1994, p. 76-85.

Research output: Contribution to journalArticle

Fraundorfer, Paul F. ; Lezama, Edwin J. ; Salazar‐Bookaman, M. Margarita ; Fertel, Richard H. ; Miller, Duane ; Feller, Dennis R. / Isomeric‐Activity ratios of trimetoquinol enantiomers on β‐adrenergic receptor subtypes : Functional and biochemical studies. In: Chirality. 1994 ; Vol. 6, No. 2. pp. 76-85.
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abstract = "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 β1‐ and β2‐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 (β1) and lung (β2) giving IARs of 115 and 389, respectively; and in E. coli expressing human β1‐ and β2‐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 β2‐AR and rat β3‐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 β3‐AR containing systems, subtypes of atypical β (or β3)‐AR may exist in adipose tissue and smooth muscle. {\circledC} 1994 Wiley‐Liss, Inc.",
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