title: Functional identification of rat atypical beta-adrenoceptors by the first beta 3-selective antagonists, aryloxypropanolaminotetralins.
abstract: 1. We have assessed the relative abilities of compounds belonging to the new aryloxypropanolaminotetralin (APAT) class and of the reference beta-adrenoceptor-blocking agent, alprenolol, to antagonize functional responses in vitro and in vivo involving atypical (beta 3) or conventional (beta 1 and beta 2) beta-adrenoceptors. 2. The range of pA2 values for three representative APATs against inhibition of spontaneous motility in the rat isolated colon by the selective beta 3-adrenoceptor agonist, SR 58611A (8.1-8.8), was well above similarly calculated values for non-competitive antagonism of guinea-pig trachea relaxation by salbutamol (beta 2, 6.5-6.9) and the atrial chronotropic response by isoprenaline (beta 1, 6.7-7.3). Alprenolol, however, was substantially more potent in antagonizing atrial (pA2, 8.2) and tracheal (pA2, 8.9) responses than SR 58611A mediated inhibition of colonic motility (pA2, 6.8). 3. Several APAT isomers with different configurations at the chiral carbons, when tested on isolated organs, presented stringent stereochemical requirements for beta 3-selectivity, including high antagonist potency-ratios between active and inactive enantiomers. 4. In vivo, the inhibition of colonic motility and the thermogenic response of brown adipose tissue elicited in rats by the selective beta 3-adrenoceptor agonists SR 58611A and BRL 37344 respectively were substantially diminished by the representative APAT, SR 59230A, at oral doses (< or = 5 mg kg-1) well below those half maximally effective (ID50) for preventing beta 1-(isoprenaline tachycardia > or = 80 mg kg-1) or beta 2-(salbutamol bronchodilatation, 44 mg kg-1) mediated responses. Alprenolol, as expected, was a less potent and nonselective antagonist of the putative beta 3-responses. 5. These findings support APATs as the first potent, orally effective selective antagonists at beta 3-adrenoceptors, and provide final unambiguous evidence that beta 3-adrenoceptors underlie inhibition of colonic motility and brown adipose tissue thermogenesis in rats.
authors.affiliation: Research Centre Sanofi Midy, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Manara
authors.forename: D
authors.initials: D
authors.lastname: Badone
authors.forename: M
authors.initials: M
authors.lastname: Baroni
authors.forename: G
authors.initials: G
authors.lastname: Boccardi
authors.forename: R
authors.initials: R
authors.lastname: Cecchi
authors.forename: T
authors.initials: T
authors.lastname: Croci
authors.forename: A
authors.initials: A
authors.lastname: Giudice
authors.forename: U
authors.initials: U
authors.lastname: Guzzi
authors.forename: M
authors.initials: M
authors.lastname: Landi
authors.forename: G
authors.initials: G
authors.lastname: Le Fur
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000403:Airway Resistance / Q000187:drug effects; D000526:Alprenolol / Q000494:pharmacology; D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects; D003106:Colon / Q000187:drug effects; D004983:Ethanolamines / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects
chemical_list: C097869:3-(2-ethylphenoxy)-1-(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanol oxalate; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D013764:Tetrahydronaphthalenes; C057368:BRL 37344; D000526:Alprenolol; C076252:amibegron