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

• Published in: European journal of pharmacology 1996-06, Vol.305 (1), p.63-71
• Main Authors: Konkar, Anish A., Fraundorfer, Paul F., Fertel, Richard H., Burkman, Allan M., Miller, Duane D., Feller, Dennis R.
• Format: Article
• Language: English
• Subjects: Adipose Tissue, Brown - metabolism; Adrenergic beta-Agonists - metabolism; Adrenergic beta-Agonists - pharmacology; Animals; Atrium, rat; Binding, Competitive; Biological and medical sciences; Brown adipose tissue, rat; Catecholaminergic system; CHO Cells; Colon - drug effects; Cricetinae; Cyclic AMP - metabolism; Distal colon, rat; Glycerol - metabolism; Heart Atria - drug effects; Heart Rate - drug effects; In Vitro Techniques; Isomeric activity ratio; Male; Medical sciences; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Pindolol - pharmacology; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta - drug effects; Receptors, Adrenergic, beta-1 - drug effects; Receptors, Adrenergic, beta-2 - drug effects; Stereoisomerism; Structure-Activity Relationship; Trachea - drug effects; Trachea, rat; Tretoquinol - analogs & derivatives; Tretoquinol - pharmacology; Trimetoquinol; β-Adrenoceptor; β-Adrenoceptor, atypical; β3-Adrenoceptor
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/0014-2999(96)00034-9

The β-adrenoceptor activity profile of trimetoquinol and its 1-benzyl halogen-substituted analogues was studied in rat tissues containing primarily β 1 (atria)-, β 2 (trachea)- and atypical β β 3 (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 β 3 - adrenoceptors than those tissues containing β 1- and β 2-adrenoceptor sites. Furthermore, this drug was a partial agonist as compared to (±)-trimetoquinol and 3′-iodotrimetoquinol on β 1-adrenoceptors. Pharmacological properties of the compounds on rat β 3-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 β 3-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 β 3-adrenoceptor ligands.