title: In vitro pharmacological properties of a series of isoprenaline derivatives.
abstract: The p-trifluoromethylanilide congener of isoprenaline, tert-butyl N-[(S)[( 4-[(R)-6-[2-(3,4-dihydroxyphenyl-2- hydroxyethyl]amino]heptanamido]phenyl]methyl][(N-methylcarbamoy l) methyl]carbamoyl]methyl]carbamate (1S,4R)-4,7,7-trimethyl-3-oxo-2- oxabicyclo[2.2.1]heptane-1-carboxylate (1:1) (Ro 17-2218) was investigated for its effects in various pharmacological tests in vitro and compared to the parent compound. As Ro 17-2218 represented a mixture of four diastereomers, the pure isomers were synthesized. They had a purity of 97-98%. By pharmacological testing of the diastereomers the highest potency was found in the 6R,2'R-isomer Ro 17-8648, while the potency of the 6S,2'S-isomer, Ro 17-9651 was lower by three orders of magnitude. The amorphous hydrochloride Ro 17-8648/001 had 1/10 the potency of the respective crystalline camphanate Ro 17-8648/003. (R)-6-[(R)-[2-(3,4-Dihydroxyphenyl)-2-hydroxyethyl]amino]-N-[4- (trifluoromethyl) phenyl]heptan amide (Ro 17-8648/003) was found to have potent beta-agonist properties with clear beta 1-selectivity in radioligand binding studies. It exerted an extremely tight binding to membrane receptors. As a full beta-agonist it elicited positive inotropic effects in isolated cardiac tissues, with a potency 10-360 times that of isoprenaline and an extremely long duration of action. Electrophysiological studies in isolated guinea-pig papillary muscles confirmed the beta 1-receptor-mediated effects of the compound.
authors.affiliation: Pharmaceutical Research Department, F. Hoffmann-La Roche & Co., Ltd., Basle, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Eigenmann
authors.forename: W P
authors.initials: WP
authors.lastname: Burkard
authors.forename: M
authors.initials: M
authors.lastname: Holck
authors.forename: H P
authors.initials: HP
authors.lastname: Märki
authors.forename: W
authors.initials: W
authors.lastname: Osterrieder
authors.forename: M
authors.initials: M
authors.lastname: Goodman
authors.forename: K L
authors.initials: KL
authors.lastname: Melmon
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D002395:Catecholamines; D004082:Dihydroalprenolol; D004280:Dobutamine / Q000378:metabolism / Q000494:pharmacology; D004285:Dogs; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007536:Isomerism; D007545:Isoproterenol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects; D011188:Potassium / Q000494:pharmacology; D011412:Propanolamines / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D017307:Xamoterol
chemical_list: D002395:Catecholamines; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D004280:Dobutamine; D004082:Dihydroalprenolol; D017307:Xamoterol; C061626:Ro 17-2218; D007545:Isoproterenol; D011188:Potassium