Biochemical activities of trimetoquinol analogs at human β1- and β3-adrenergic receptors

Anish A. Konkar, Victor I. Nikulin, Joseph De Los Angeles, Seoung Soo Hong, Richard H. Fertel, Duane Miller, Dennis R. Feller

Research output: Contribution to journalArticle

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Abstract

The biochemical activities of trimetoquinol (TMQ) analogs were evaluated at the human β1- and β3-adrenergic receptor (AR) subtypes expressed in Chinese hamster ovary cells. In radioligand binding assays, the 1-benzyl iodine-substituted analogs exhibited higher binding affinities at both β1- and β3-AR subtype as compared to TMQ. In cAMP accumulation assays, these analogs exhibited high potencies at both β1- and β3-AR. The 3′,5′-diiodo-4′-amino analog of TMQ was the most potent β3-AR agonist, 17-fold more potent at the β3-AR versus the β1-AR. Masking of the 6,7-dihydroxy group of the catechol ring of 3′,5′-diiodo-4′-acetamido analog of TMQ, a potent β1- and β3-AR agonist, abolished activity at both β-AR subtypes. Furthermore, substitution of a strong electron withdrawing group such as the trifluoromethyl moiety at the 1-benzyl ring of TMQ dramatically decreased potency at β1- and β3-AR compared to TMQ. Replacement of the 1-benzyl ring of TMQ with a naphthalene ring did not alter affinity but reduced potency of resulting 1-naphthylmethyl and 2-naphthylmethyl analogs at β1- and β3-AR compared to TMQ. Our results define the structural and electronic properties of substituents on TMQ necessary for potent activation of β1- and β3-AR and suggest that further modifications of the 1- benzyl iodine-substituted analogs may yield potent β3-AR agonists.

Original languageEnglish (US)
Pages (from-to)45-55
Number of pages11
JournalPharmacology
Volume62
Issue number1
DOIs
StatePublished - Jan 17 2001

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Tretoquinol
Adrenergic Receptors
Adrenergic Agonists
Iodine
Radioligand Assay
Cricetulus
Ovary

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Konkar, A. A., Nikulin, V. I., De Los Angeles, J., Hong, S. S., Fertel, R. H., Miller, D., & Feller, D. R. (2001). Biochemical activities of trimetoquinol analogs at human β1- and β3-adrenergic receptors. Pharmacology, 62(1), 45-55. https://doi.org/10.1159/000056071

Biochemical activities of trimetoquinol analogs at human β1- and β3-adrenergic receptors. / Konkar, Anish A.; Nikulin, Victor I.; De Los Angeles, Joseph; Hong, Seoung Soo; Fertel, Richard H.; Miller, Duane; Feller, Dennis R.

In: Pharmacology, Vol. 62, No. 1, 17.01.2001, p. 45-55.

Research output: Contribution to journalArticle

Konkar, AA, Nikulin, VI, De Los Angeles, J, Hong, SS, Fertel, RH, Miller, D & Feller, DR 2001, 'Biochemical activities of trimetoquinol analogs at human β1- and β3-adrenergic receptors', Pharmacology, vol. 62, no. 1, pp. 45-55. https://doi.org/10.1159/000056071
Konkar, Anish A. ; Nikulin, Victor I. ; De Los Angeles, Joseph ; Hong, Seoung Soo ; Fertel, Richard H. ; Miller, Duane ; Feller, Dennis R. / Biochemical activities of trimetoquinol analogs at human β1- and β3-adrenergic receptors. In: Pharmacology. 2001 ; Vol. 62, No. 1. pp. 45-55.
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