Molecular Pharmacology, Vol 18, 461-467, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Structure-Activity Relationships of Eseroline and Morphine: Ab Initio Quantum-Chemical Study of the Electrostatic Potential and of the Interaction Energy with Water

¹ Dipartimento di Farmacologia dell’Universita, Viale Morgagni 65, 50134 Firenze, Italy
² Department of Anesthesiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and Department of Chemistry, The Johns Hopkins University, Baltimore, Maryland 21218
³ Laboratorio di Chimica Quantistica ed Energetica Molecolare del C.N.R., Via Risorgimento 35, 56100 Pisa, Italy

Ab initio SCF-MO-LCAO calculations of the electrostatic potential and analytical calculations of the interaction energy with water have been performed for two analgesic molecules: eseroline and morphine. The nature of the calculations and the structure-activity relationships have been discussed and the theoretical results have been compared with the experimental binding affinities to the opiate receptor. The calculations show that the reactivity properties of the aminic N of eseroline and morphine are very similar, while significant differences were found for the electrostatic potential and water affinity of N₅, benzene, and phenolic OH. These results can explain the lower binding affinity of eseroline to the receptor with respect to that of morphine, they agree with experimental data on the binding affinity of analgesics to the receptor, and they confirm a molecular model of the analgesic-receptor interaction which has been suggested on the basis of experimental data.

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ACKNOWLEDGMENTS The authors are very indebted to Prof. A. Bartolini, who communicated the results on eseroline prior to publication. We should like to thank Drs. M. Braude and H. Willette of the NIDA, Division of Research, Biomedical Research Branch, for their perceptiveness in visualizing the contributions such theoretical studies could make.