X-ray analisis, theoretical studies and a-adrenergic biopharmacological properties of 1-(2,5-dimethoxyphenyl)-2-aminoethanol and its morpholine analogue

The alpha(1)- and alpha(2)- adrenergic properties of 1-(2,5-dimethoxyphenyl)-2-aminoethanol 3a and its derivative in which the ethanolaminic side chain is cyclized to morpholine 3b were evaluated in vitro, both by radioligand binding assays and by functional tests on isolated preparations. The pharmacological activity on the alpha(1)-receptors passes from stimulant for 3a to blocking for 3b, whereas on the alpha(2)-receptors, it remains stimulant for both 3a and 3b. This behaviour is different from that of other a-adrenergic agents like norepinephrine (1a), which shows the same pharmacological profile on both the alpha(1)- and alpha(2)-receptors than its morpholine analogue, 1b. An X-ray crystallographic analysis performed on 3a and 3b, together with a theoretical conformational analysis performed on 1a,b and 3a,b suggest an explanation for the pharmacological properties observed in terms of rotameric positions of the phenyl ring.