Molecular orbital calculations of proton transfer energetics in model systems: the interaction of opiate agonists and antagonists with opiate receptors.

Semiempirical (CNDO) molecular orbital calculations, based on a previously investigated morphine-receptor clastic-binding system, were performed using a series of ethyl and propyl amines as models for the analgesic receptor. Trimethyl and dimethyl amines were chosen to represent the opiate and noropiate agonist molecules. The opiate antagonist molecules, levallorphan, naloxone, nalorphine, and pentazocine were represented by a series of allyl and dimethylallyl amines. The results using these systems paralleled those of our previous investigations. The potential energy curves for all the systems studied had two minima at an internuclear distance of greater than 0.275 nm. At 0.2731 nm (the optimized N-N distance), the potential energy curve of some systems had single minima. The agonist systems studied had optimum energy curves for the conformer in which the (drug nitrogen-hydrogen) bond is equatorial. The noropiate model had the greatest transfer potential, an optimal condition for analgesic activity. The antagonist drug receptor models had energy curves that indicated a decreased proton transfer barrier that was similar to the noropiate case (although no delta E was obtained). The two largest models studied had energy curves that indicated decreased or inhibited proton transfer. The systems investigated had small deprotonation barriers, indicating deprotonation would most likely occur following protonation of the receptor.