Eigenmann R, Burkard W P, Holck M, Märki H P, Osterrieder W, Goodman M, Melmon K L
Pharmaceutical Research Department, F. Hoffmann-La Roche & Co., Ltd., Basle, Switzerland.
Arzneimittelforschung. 1989 Aug;39(8):842-7.
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.
对异丙肾上腺素的对三氟甲基苯胺同系物，叔丁基N-[(S)[(4-[(R)-6-[2-(3,4-二羟基苯基-2-羟乙基]氨基]庚酰胺基]苯基]甲基][(N-甲基氨基甲酰基)甲基]氨基甲酸酯(1S,4R)-4,7,7-三甲基-3-氧代-2-氧杂双环[2.2.1]庚烷-1-羧酸酯(1:1)(Ro 17-2218)进行了体外各种药理学试验研究，并与母体化合物进行了比较。由于Ro 17-2218是四种非对映异构体的混合物，因此合成了纯异构体。它们的纯度为97-98%。通过对非对映异构体的药理学测试，发现6R,2'R-异构体Ro 17-8648的效力最高，而6S,2'S-异构体Ro 17-9651的效力低三个数量级。无定形盐酸盐Ro 17-8648/001的效力是相应结晶樟脑酸盐Ro 17-8648/003的1/10。(R)-6-[(R)-[2-(3,4-二羟基苯基)-2-羟乙基]氨基]-N-[4-(三氟甲基)苯基]庚酰胺(Ro 17-8648/003)在放射性配体结合研究中被发现具有强效β-激动剂特性且具有明显的β1选择性。它与膜受体结合极其紧密。作为一种完全的β-激动剂，它在离体心脏组织中引起正性肌力作用，效力是异丙肾上腺素的10-360倍，且作用持续时间极长。在离体豚鼠乳头肌上进行的电生理研究证实了该化合物的β1受体介导作用。
