In vitro pharmacological properties of a series of isoprenaline derivatives

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.