CONFORMATIONAL EFFECTS ON THE ACTIVITY OF DRUGS .17. CONFORMATIONALLYRESTRAINED ANALOGS OF SYMPATHOMIMETIC CATECHOLAMINES - SYNTHESIS AND ADRENERGIC ACTIVITY OF TETRAHYDROBENZOCYCLOHEPTENE DERIVATIVES

The tetrahydrobenzocycloheptene analogs 7-10 of norepinephrine (NE, 1) and isoproterenol (ISO, 2) were synthesized and tested for their alph a- and beta-adrenergic properties by means of functional tests on isol ated preparations. The conformational profile of 7 was studied by mean s of theoretical calculations. The results of the pharmacological test s showed that, in general, the cyclization of NE (1) and ISO (2) to th eir semirigid analogs 7-10 leads to a marked reduction or even to the disappearance of the adrenergic activity of the corresponding open-cha in compounds 1 and 2. Possible rationalizations of the differences in alpha(2)-adrenergic activity shown by the benzocycloheptene derivative 7 and the corresponding previously studied tetrahydronaphthalene deri vative 3 are suggested on the basis of a comparison of their stereostr uctures in the preferred conformations.