Molecular Pharmacology, Vol 9, 486-494, Copyright © 1973 by the American Society for Pharmacology and Experimental Therapeutics

A Molecular Orbital Study of Norepinephrine and 3,4-Dihydroxyphenethylamine: a Re-evaluation of Structure-Activity Relationships in Norepinephrine

¹ Microanalytical Services and Instrumentation Section, Laboratory of Chemistry, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Bethesda, Maryland 20014
² Heuristics Laboratory, Division of Computer Research and Technology, National Institutes of Health, Bethesda, Maryland 20014
³ Medicinal Chemistry Section, Laboratory of Chemistry, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Bethesda, Maryland 20014

Complete neglect of differential overlap (CNDO) calculations show that protonated (14R)norepinephrine can exhibit four minimum energy conformations, two trans and two gauche. Small relative energy differences between the gauche and trans forms were noted, in favor of the gauche forms. Interatomic distances in the two gauche and in the two trans forms were different. The minimum energy conformations of possible importance in the uptake process of norepinephrine at adrenergic nerve terminals of mouse cardiac tissue were found to exhibit a distance of approximately 6A between two heteroatoms. A likely distinction between (14R)- and (14S)-norepinephrine is postulated. CNDO calculations on protonated dopamine and dopamine free base indicated their existence in three minimum energy conformations, one trans and two gauche. Again, the approximately 6A distance between possibly biologically important atoms was noted in one of the gauche conformations. Calculations on the meta and para anions of dopamine free base indicated that the meta anion was more stable than the para anion, and that both anions displayed the same minimum energy conformations as dopamine free base. The net electronic charge distributions and interatomic distances, in minimum energy conformations, are listed for all these compounds.

Note:
ACKNOWLEDGMENT We are indebted to R. J. Feldmann for his assistance with the Adage AGT-30 and the X-ray modeling system, to Dr. R. E. Alving for many helpful conversations, and to Dr. R. Rupin (Nahal Soreq, Atomic Researchlu Center, Israel) for his aid in the conversion of the CNDO program to single precision.