Biochemical and functional characterization of 1-benzyl substituted trimetoquinol affinity analogs on rat and human β-adrenoceptors

Ratna C. Mehta, Margarita M. Salazar-Bookaman, Richard H. Fertel, Joseph De Los Angeles, Victor I. Nikulin, Paul F. Fraundorfer, Duane Miller, Dennis R. Feller

Research output: Contribution to journalArticle

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Abstract

The site of interaction for the 1-(3',4',5'-trimethoxybenzyl) group of trimetoquinol (TMQ) with β-adrenoceptors (β-ARs) is important for the rational design of highly potent and β3-AR-selective analogs. 1-Benzyl ring-substituted TMQ analogs were evaluated for binding affinities and biochemical activities (cyclic AMP accumulations) in Chinese hamster ovary (CHO) cells expressing the rat and human β3-AR, and for functional activities on isolated rat tissues. Binding affinities (K(i) ~ 0.055 to 1.5 μM) for the rat β3-AR and potencies for adenylyl cyclase activation (K(act) ~ 0.43 to 2.5 nM) of the 3'-monoiodo or 3',5'-diiodo derivatives with 4'-isothiocyanato-, 4'-amino, 4'-acetamido, or 4'-α-haloacetamido substitutions were higher than those of (-)-isoproterenol, and comparable to those of BRL 37344 [(±)-(R*,R*-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]-acetic acid sodium]. A similar rank order of binding affinities (K(i) ~ 0.11 to 2.5 μM) and potencies (K(act) ~ 0.45 to 9.5 nM) was obtained for TMQ analogs on the human β3-AR. The 4'-acetamido and 4'-α-chloroacetamido analogs of 3',5'-diiodoTMQ were more potent than (-)-isoproterenol in rat atria (β1-AR) and rat trachea (β2-AR) and exhibited partial agonist activities, whereas full agonist activities were observed in rat esophageal smooth muscle (EC50 ~ 2-8 nM, β3-AR). 4'-α-Chloroacetamido-3',5'-diiodoTMQ-mediated chronotropic responses in atria were sustained and resistant to washout. Further, the 4'-α-chloroacetamido and 4'-α-bromoacetamido analogs of 3',5'-diiodoTMQ demonstrated significant concentration-dependent irreversible binding to the rat β3-AR. Reversible β-AR agonists such as (-)-isoproterenol, BRL 37344, and 4'-acetamido-3',5'-diiodoTMQ or nucleophilic l-amino acids (lysine, glutathione, cysteine) did not protect against this irreversible binding. Thus, the lipophilic 1-benzyl ring of TMQ analogs interacts with a hydrophobic region of the β-AR that may represent an exo-site or an allosteric binding site. Copyright (C) 2000 Elsevier Science Inc.

Original languageEnglish (US)
Pages (from-to)517-529
Number of pages13
JournalBiochemical Pharmacology
Volume59
Issue number5
DOIs
StatePublished - Mar 1 2000

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Tretoquinol
Adrenergic Receptors
Rats
Isoproterenol
Allosteric Site
Cricetulus
Trachea
Adenylyl Cyclases
Cyclic AMP
Lysine
Glutathione
Cysteine
Smooth Muscle
Muscle
Ovary
Substitution reactions
Sodium
Chemical activation
Binding Sites
Cells

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Cite this

Mehta, R. C., Salazar-Bookaman, M. M., Fertel, R. H., De Los Angeles, J., Nikulin, V. I., Fraundorfer, P. F., ... Feller, D. R. (2000). Biochemical and functional characterization of 1-benzyl substituted trimetoquinol affinity analogs on rat and human β-adrenoceptors. Biochemical Pharmacology, 59(5), 517-529. https://doi.org/10.1016/S0006-2952(99)00376-7

Biochemical and functional characterization of 1-benzyl substituted trimetoquinol affinity analogs on rat and human β-adrenoceptors. / Mehta, Ratna C.; Salazar-Bookaman, Margarita M.; Fertel, Richard H.; De Los Angeles, Joseph; Nikulin, Victor I.; Fraundorfer, Paul F.; Miller, Duane; Feller, Dennis R.

In: Biochemical Pharmacology, Vol. 59, No. 5, 01.03.2000, p. 517-529.

Research output: Contribution to journalArticle

Mehta, RC, Salazar-Bookaman, MM, Fertel, RH, De Los Angeles, J, Nikulin, VI, Fraundorfer, PF, Miller, D & Feller, DR 2000, 'Biochemical and functional characterization of 1-benzyl substituted trimetoquinol affinity analogs on rat and human β-adrenoceptors', Biochemical Pharmacology, vol. 59, no. 5, pp. 517-529. https://doi.org/10.1016/S0006-2952(99)00376-7
Mehta, Ratna C. ; Salazar-Bookaman, Margarita M. ; Fertel, Richard H. ; De Los Angeles, Joseph ; Nikulin, Victor I. ; Fraundorfer, Paul F. ; Miller, Duane ; Feller, Dennis R. / Biochemical and functional characterization of 1-benzyl substituted trimetoquinol affinity analogs on rat and human β-adrenoceptors. In: Biochemical Pharmacology. 2000 ; Vol. 59, No. 5. pp. 517-529.
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