Conformationally restricted dopamine congeners--a molecular mechanics-based study

Potential energies of several systems containing the phenylethylamine fragment were computed by the QCFF/PI method and some of them also by the PCILO method. The systems considered are: octahydrobenzo [f]- and [g]-quinolines, aporphine, 1-phenylbenzazepine, 4-phenyltetrahydroisoquinoline, 3-phenylpiperidine and 9-aminodihydrophenanthrene. No common set of torsion angles defining the stereostructure around the amine head is apparent if only the lowest energy conformations are considered. Leaving out the orientation of the N-CH3 group, and considering also some higher energy conformations, two groups of systems may be formed, A and B, the members of which are congruent amongst themselves in parameters defining the spatial relations of the amine site and the catechol ring, and in the orientation of the N+-H bond. The stereostructure of the rigid representatives of group A is postulated to be the one required by the brain and cardioaccelerator nerve receptor. A corresponding postulate for the vascular bed DA receptors cannot be made since systems forming group B, the derivatives of which are active both on brain and vascular bed receptors, have more conformation space and, moreover, they carry additional potential anchoring groups.