Molecular determinants for drug-receptor interactions. 12. Molecular orbital studies on opioid analgesics N-allyl-Normetazocine and nalorphine: Conformations and electrostatic molecular potentials

Abstract

A conformational study of the mixed agonist-antagonist opioid analgesics N-allyl-N-normetazocine (NAM) and nalorphine (NLP), both as free bases and N-protonated species (NAMH + , NLPH + ), was performed using semiempirical MO theoretical calculations AM1 type. The recognition of these opiate drugs by the pertinent receptors and their interactions with the receptor at the molecular level were investigated and discussed by the analyses of the conformational results as well as of the electrostatic molecular potential (EMP) contour maps calculated for the interacting active NAMH + and NLPH + species in their minimum energy conformations. Four preferred N-allyl orientations, which were almost similar for both drugs, were found for the conformationally more restricted ionic structures. Each set of four conformations was consisting of two pairs of equally populated “conformational enantiomers” relative to the involved N-allyl piperidine molecular fragment. The calculations also indicated the differences in energy barriers that exist between the two ionic and non-ionic states. Eight and seven energy minima were located for NAM and NLP, respectively. The lowest energy minima were the most populated ones, i.e. 37% and 44% in NAM and NLP, respectively. The EMP contour maps allowed to establish that in the N-substituted piperidine ring fragment the isopotential curves localization is the same for corresponding conformations in both NAMH + and NLPH + . The changes of the structure of the larger rigid molecular backbone as well as of the conformation of the N-allyl groups do not affect the EMP's relative to the backbone of NAMH + and NLPH + . Therefore the most suggestive feature of the results was that, in spite of the wide variation in structure and size of the molecular skeletons, the prerequisite for analogues activity functions in NAMH + and NLPH + appeared the similar preferred conformations and the corresponding electrostatic potentials of their N-allyl piperidine moiety.