title: Pharmacological activities of trimetoquinol and 1-benzyl halogen-substituted analogues on rat beta-adrenoceptor subtypes.
abstract: The beta-adrenoceptor activity profile of trimetoquinol and its 1-benzyl halogen-substituted analogues was studied in rat tissues containing primarily beta 1 (atria)-, beta 2 (trachea)- and atypical beta/beta 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 beta-adrenoceptor subtypes. In functional assays, 3'-iodotrimetoquinol was a potent activator of all beta-adrenoceptor subtypes. 3',5'-Diiodotrimetoquinol was 10-fold more potent as an agonist in tissues containing atypical beta/beta 3-adrenoceptors than those tissues containing beta 1- and beta 2-adrenoceptor sites. Furthermore, this drug was a partial agonist as compared to (+/-)-trimetoquinol and 3'-iodotrimetoquinol on beta 1-adrenoceptors. Pharmacological properties of the compounds on rat beta 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 beta 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 beta 3-adrenoceptor ligands.
authors.affiliation: College of Pharmacy, Ohio State University, Columbus 43210, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Konkar
authors.forename: P F
authors.initials: PF
authors.lastname: Fraundorfer
authors.forename: R H
authors.initials: RH
authors.lastname: Fertel
authors.forename: A M
authors.initials: AM
authors.lastname: Burkman
authors.forename: D D
authors.initials: DD
authors.lastname: Miller
authors.forename: D R
authors.initials: DR
authors.lastname: Feller
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D003106:Colon / Q000187:drug effects; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D005990:Glycerol / Q000378:metabolism; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010869:Pindolol / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects; D014213:Tretoquinol / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D010869:Pindolol; D000242:Cyclic AMP; D014213:Tretoquinol; D005990:Glycerol