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 provided information about the steric requirements for the direct activation of a1, a2,& and ,f32 adrenoceptors, respectively. The l-(aminomethyl)-6,7-dihydroxyisochromans1 1 and 12 and the 1-(aminomethyl)- 5,6-dihydroxyisochromans1 3 and 14 (1-AMDICs) are two different types of semirigid analogs of NE and ISO. The a1, a2, @I, and 82 adrenergic properties of the 1-AMDICs 11-14 were evaluated in vitro, both by radioligand binding assays and by functional testa on isolated preparations, and were compared with those of their parent compounds (NE and ISO). The results of a conformational study carried out by means of both lH NM'R spectrometry and theoretical calculations indicated that, in these 1-AMDICs, the presumed active groups (aryl moiety, amine nitrogen and benzylic ethereal oxygen) we in a spatial relationship corresponding to the one found for NE and IS0 in their preferred conformations, which also proved to be the pharmacophoric conformation in the models A-C. By means of a comparison of the stereostructures of the 1-AMDICs 11-14 with their biopharmacological properties, it was possible to obtain a further definition of the model B with respect to the activation of the a2 adrenoceptors; the superimposition of the 1-AMDICs 11 and 12 with the molecular model C made it possible to detect an area of the /&adrenergic receptors which might hinder the fit of adrenergic drugs that are analogs of catecholamines with these receptors.