CONFORMATIONALLY RESTRAINED 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 alpha- and beta-adrenergic properties by means of functional tests on isolated preparations. The conformational profile of 7 was studied by means of theoretical calculations. The results of the pharmacological tests showed that, in general, the cyclization of NE (1) and ISO (2) to their semirigid analogs 7-10 leads to a marked reduction or even to the disappearance of the adrenergic activity of the corresponding open-chain 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 derivative 3 are suggested on the basis of a comparison of their stereostructures in the preferred conformations.