CONFORMATIONALLY RESTRAINED BETA-BLOCKING OXIME ETHERS .2. SYNTHESIS AND BETA-ADRENERGIC PROPERTIES OF DIASTEREOISOMERIC ANTI AND SYN L-SUBSTITUTED)ISOXAZOLIDINYL)-N-ALKYLETHANOLAMINES

The diastereoisomeric 2-(5'-(3'-aryl)isoxazolidinyl) ethanolamines 1c- h-4c-h were synthesized as analogs of the corresponding P-blocking iso xazolines unsubstituted on the aromatic ring 1a-4a, with the aim of ch ecking the effects on the adrenergic properties of the insertion of a methoxy group or a chlorine atom in the ortho, meta or para position o f the phenyl ring of 1a-4a. The relative configurations of 1c-h-4c-h w ere assigned on the basis of their H-1-NMR spectral characteristics. T he new isoxazolines 1c-h-4c-h were tested for their affinity towards b eta(1)- and beta(2)-adrenoceptors by radioligand binding experiments; compounds showing the highest affinity were also assayed for their bet a-adrenergic activity by functional tests on isolated preparations. Th e results showed that most of the new compounds (1c-h-4c-h) possess a slightly better capacity to interact with the beta-receptors, compared with the corresponding analogs unsubstituted on the phenyl ring (1a-4 a), and that the substitution that leads to compounds with the best pr operties is the one with the chlorine atom. Quantum mechanical calcula tions carried out in order to look for possible correlations between t he beta-adrenergic properties and the conformational and electronic ch aracteristics induced by the presence of the substituents on the pheny l ring of compounds of types 1-4 do not suggest any reasonable explana tion for the trend of the affinity data.