Pharmacological activities of trimetoquinol and 1-benzyl halogen-substituted analogues on rat β-adrenoceptor subtypes

Anish A. Konkar, Paul F. Fraundorfer, Richard H. Fertel, Allan M. Burkman, Duane Miller, Dennis R. Feller

Research output: Contribution to journalArticle

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Abstract

The β-adrenoceptor activity profile of trimetoquinol and its 1-benzylhalogen-substituted analogues was studied in rat tissues containing primarily β1 (atria)-, β2 (trachea)- and atypical β/β3 (distal colon and brown adipose tissue)-adrenoceptors. Functional biological activity resided in the (-)-isomer of trimetoquinol which was 112-, 275-, 372- and 513-fold more potent than (+)-trimetoquinol in trachea, right atria, distal colon and brown adipose tissue, respectively. (±)-Trimetoquinol was equally or slightly less active than (-)-trimetoquinol. The 1-benzyl halogen-substituted analogues of trimetoquinol exhibited differential activation of β-adrenoceptor subtypes. In functional assays, 3'-iodotrimetoquinol was a potent activator of all β-adrenoceptor subtypes. 3',5,-Diiodotrimetoquinol was 10-fold more potent as an agonist in tissues containing atypical β/β3-adrenoceptors than those tissues containing β1- and β2-adrenoceptor sites. Furthermore, this drug was a partial agonist as compared to (±)-trimetoquinol and 3'-iodotrimetoquinol on β1-adrenoceptors. Pharmacological properties of the compounds on rat β3-adrenoceptors expressed in Chinese hamster ovary (CHO) cells were consistent with results observed in functional assays. 3',5'-Diiodotrimetoquinol possessed the greatest potency for activation of adenylyl cyclase. Rank order of affinity for rat β3-adrenoceptor was 3'-iodotrimetoquinol = 3',5'-diiodotrimetoquinol > (±)-trimetoquinol > (-)-isoprenaline. These results suggest that 3',5'-diiodotrimetoquinol is a promising drug for further chemical modification in the development of selective β3-adrenoceptor ligands.

Original languageEnglish (US)
Pages (from-to)63-71
Number of pages9
JournalEuropean Journal of Pharmacology
Volume305
Issue number1-3
DOIs
StatePublished - Jun 3 1996

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Tretoquinol
Halogens
Adrenergic Receptors
Pharmacology
Brown Adipose Tissue
Trachea
Colon
Cricetulus
Heart Atria
Isoproterenol
Adenylyl Cyclases
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Pharmacological activities of trimetoquinol and 1-benzyl halogen-substituted analogues on rat β-adrenoceptor subtypes. / Konkar, Anish A.; Fraundorfer, Paul F.; Fertel, Richard H.; Burkman, Allan M.; Miller, Duane; Feller, Dennis R.

In: European Journal of Pharmacology, Vol. 305, No. 1-3, 03.06.1996, p. 63-71.

Research output: Contribution to journalArticle

Konkar, Anish A. ; Fraundorfer, Paul F. ; Fertel, Richard H. ; Burkman, Allan M. ; Miller, Duane ; Feller, Dennis R. / Pharmacological activities of trimetoquinol and 1-benzyl halogen-substituted analogues on rat β-adrenoceptor subtypes. In: European Journal of Pharmacology. 1996 ; Vol. 305, No. 1-3. pp. 63-71.
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