β-adrenoceptor subtype activities of trimetoquinol derivatives

Biochemical studies on human β-adrenoceptors expressed in Chinese hamster ovary cells

Anish A. Konkar, Sandeep S. Vansal, Gamal Shams, Paul F. Fraundorfer, Wei Ping Zheng, Victor I. Nikulin, Joseph De Los Angeles, Richard H. Fertel, Duane Miller, Dennis R. Feller

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Abstract

The β-adrenoceptor activities of trimetoquinol (TMQ) isomers and selected derivatives were evaluated on human β-adrenoceptor subtypes expressed in Chinese hamster ovary cells. In cAMP accumulation assays, (-)- TMQ was 214-, 281-, and 776-fold more potent than (+)-TMQ at stimulating β1-, β2-, and β3-adrenoceptor subtypes, respectively. In radioligand binding assays, (-)-TMQ exhibited 123-, 331-, and 5-fold greater affinity than (+)-TMQ for β1-, β2-, and β3-adrenoceptor subtypes, respectively. (-)-TMQ and (±)-TMQ activated the human β3-adrenoceptor with an 8.2- and 3.4-fold greater efficacy, respectively, than the reference β-adrenoceptor agonist (-)-isoproterenol (efficacy = 1). The 3',5'-diiodo analogs of TMQ were partial agonists of the β2-adrenoceptor relative to (-)-isoproterenol, and their potencies were 5- to 10-fold higher at the β3-adrenoceptor as compared with β1-adrenoceptors. Modification of the catechol (6,7- dihydroxy) nucleus, such as replacement of the 7-hydroxy group with a chloro group (7-chloroTMQ); ring fluorination (8-fluoro and 5,8-difluoro analogs), or preparation of bioisosteric tetrahydrothiazolopyridine (THP) derivatives of TMQ yielded compounds that displayed partial agonist activity (relative to (-)-isoproterenol) or were inactive at the β2-adrenoceptor and exhibited β3-adrenoceptor-selective stimulation compared with the β1-adrenoceptor. Furthermore, the 3',5'-diiodo-4'-methoxybenzylTHP derivative of TMQ was 65- fold more potent than the corresponding 3',4',5'-trimethoxybenzylTHP at the human β3-adrenoceptor. Our results indicate that 6,7-dihydroxy-catechol- modified and 1-benzyl halogen-substituted derivatives of TMQ represent promising leads for the development of β3-adrenoceptor-selective agonists.

Original languageEnglish (US)
Pages (from-to)875-883
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume291
Issue number2
StatePublished - Nov 1 1999

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Tretoquinol
Cricetulus
Adrenergic Receptors
Ovary
Isoproterenol
Radioligand Assay

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Konkar, A. A., Vansal, S. S., Shams, G., Fraundorfer, P. F., Zheng, W. P., Nikulin, V. I., ... Feller, D. R. (1999). β-adrenoceptor subtype activities of trimetoquinol derivatives: Biochemical studies on human β-adrenoceptors expressed in Chinese hamster ovary cells. Journal of Pharmacology and Experimental Therapeutics, 291(2), 875-883.

β-adrenoceptor subtype activities of trimetoquinol derivatives : Biochemical studies on human β-adrenoceptors expressed in Chinese hamster ovary cells. / Konkar, Anish A.; Vansal, Sandeep S.; Shams, Gamal; Fraundorfer, Paul F.; Zheng, Wei Ping; Nikulin, Victor I.; De Los Angeles, Joseph; Fertel, Richard H.; Miller, Duane; Feller, Dennis R.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 291, No. 2, 01.11.1999, p. 875-883.

Research output: Contribution to journalArticle

Konkar, AA, Vansal, SS, Shams, G, Fraundorfer, PF, Zheng, WP, Nikulin, VI, De Los Angeles, J, Fertel, RH, Miller, D & Feller, DR 1999, 'β-adrenoceptor subtype activities of trimetoquinol derivatives: Biochemical studies on human β-adrenoceptors expressed in Chinese hamster ovary cells', Journal of Pharmacology and Experimental Therapeutics, vol. 291, no. 2, pp. 875-883.
Konkar, Anish A. ; Vansal, Sandeep S. ; Shams, Gamal ; Fraundorfer, Paul F. ; Zheng, Wei Ping ; Nikulin, Victor I. ; De Los Angeles, Joseph ; Fertel, Richard H. ; Miller, Duane ; Feller, Dennis R. / β-adrenoceptor subtype activities of trimetoquinol derivatives : Biochemical studies on human β-adrenoceptors expressed in Chinese hamster ovary cells. In: Journal of Pharmacology and Experimental Therapeutics. 1999 ; Vol. 291, No. 2. pp. 875-883.
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AU - Shams, Gamal

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AU - Zheng, Wei Ping

AU - Nikulin, Victor I.

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AU - Fertel, Richard H.

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AU - Feller, Dennis R.

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