CONFORMATIONALLY RESTRAINED ANALOGS OF SYMPATHOMIMETIC CATECHOLAMINES- SYNTHESIS, CONFORMATIONAL-ANALYSIS, AND ADRENERGIC ACTIVITY OF ISOCHROMAN DERIVATIVES

In previous papers dealing with the study of the conformations and the biopharmacological activity of conformationally restrained analogs of sympathomimetic catecholamines (NE and ISO), proposals were advanced for the three-dimensional molecular models A, B, and C; these models p rovided information about the steric requirements for the direct activ ation of alpha1, alpha2, beta1, and beta2 adrenoceptors, respectively. The 1-(aminomethyl)-6,7-dihydroxyisochromans 11 and 12 and the 1-(ami nomethyl)-5,6-dihydroxyisochromans 13 and 14 (1-AMDICs) are two differ ent types of semirigid analogs of NE and ISO. The alpha1, alpha2, beta 1, and beta2 adrenergic properties of the 1-AMDICs 11-14 were evaluate d in vitro, both by radioligand binding assays and by functional tests on isolated preparations, and were compared with those of their paren t compounds (NE and ISO). The results of a conformational study carrie d out by means of both H-1 NMR spectrometry and theoretical calculatio ns indicated that, in these 1-AMDICs, the presumed active groups (aryl moiety, amine nitrogen and benzylic ethereal oxygen) are in a spatial relationship corresponding to the one found for NE and ISO in their p referred conformations, which also proved to be the pharmacophoric con formation in the models A-C. By means of a comparison of the stereostr uctures of the I-AMDICs 11-14 with their biopharmacological properties , it was possible to obtain a further definition of the model B with r espect to the activation of the alpha2 adrenoceptors; the superimposit ion of the 1-AMDICs 11 and 12 with the molecular model C made it.possi ble to detect an area of the beta-adrenergic receptors which might hin der the fit of adrenergic drugs that are analogs of catecholamines wit h these receptors.