Chem.-BioL Interactions, 30 (1980) 79--85 © Elsevier/North-Holland ScientificPublishers Ltd. 79 QUANTUM MECHANICAL CONFORMATIONAL ANALYSIS OF HETEROCYCLIC ANALOGUES OF NOREPHEDRINE JOSI~ KANETI, DIMITRIAMIHAILOVA a, KITSCHKAFArFONDZIEVA a and LUBOMIR ZHELJAZKOV b Institute of Organic Chemistry, Bulgarian Academy of Sciences, 1113 Sofia, aFaculty of Pharmacy, Academy of Medicine, 1000 Sofia and bDepartment of Pharmaceutical Chem- istry, Institute of Chemical Technology, 1156 Sofia (Bulgaria) (ReceivedJuly 16th, 1979) (Accepted November1st, 1979) SUMMARY Studies on the conformation of several structural analogues of norephe- drine, thiophene, carbazole and fumn, were carried out using the differ- ential PCILO method. The e~thro-forms of these compounds possess minima on the conformation map corresponding to a gauche conformation with synclinal H-atoms. This result is in good agreement with the proton- proton coupling constants found in previous NMR-studies. ~H-NMR-studies suggest for the threo-isomers of the studied molecules an equilibrium between the tran~ and gache-conformations of the ethanolamine chain. Present calculations agree fairly well with this result. All the studied mole- cules possess conformational minima corresponding to the folded form of the side chain believed responsible for the physiological activity of nor- ephedrine. The distances between 'N' and 'O' atoms in this preferred con- formation correspond to the model proposed by Kier and l~nman for a-adrenergic receptors. INTRODUCTION The pronounced neurotropic activity of phenylethylamine derivatives determines the extensive physico-ehemical and pharmacological studies of these compounds. A number of laboratories are dealing with the syn- thesis of different structural analogues of the endogenous amines. There is no doubt therefore that a possibility to predict at least qualitatively the effect of electronic and conformational properties on the activity of these compounds would be highly significant. The effect of aromatic substituents on the reactivity of dopamine-~- hydroxylase and phenethanolamine-N-methyltransfemse substrates is stud- ied by Fujita and Ban [1]. Kier [2] and Pullman et al. [3] analysed the