Molecular Pharmacology, Vol 16, 1031-1039, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

[¹³C]NMR Chemical Shifts and Calculated Electronic Structures of Serotonin Congeners: Relation to Biological Activity

¹ Max Planck Institut, D-4600 Dortmund, Germany; and Department of Pharmacology, Mount Sinai School of Medicine, New York, N. Y. 10029
² Gesellshaft fur Biotechnologische Forschung, D-5300 Braunschweig, Germany
³ Department of Pharmacology, Mount Sinai School of Medicine, New York, N.Y. 10029

[¹³C]NMR and quantum mechanical calculations of the electronic structure of some substituted tryptamines were applied to study the molecular determinants for the activity of these compounds on the LSD/serotonin receptor. A good correlation was observed between the measured [¹³C]chemical shifts and the gross atomic charges obtained from ab-initio and near ab-initio (pseudopotential) calculations. These parameters, however, did not correlate with the biological activity of the compounds measured by their potency in contracting the rat fundus or by their ability to displace D-LSD from a high-affinity binding site in brain homogenates from guinea pig. For example, 5-fluorotryptamine (5-FT) resembles tryptamine more than serotonin in its biological potency but is most similar to serotonin in both the measured [¹³C]chemical shifts and the calculated charge distribution. However, the frontier electron density maps above the indole portion of 5-FT bear a striking resemblance to those of tryptamine. The similar biological potency of 5-FT and tryptamine is in full accord with these findings and with results from our previous work from which the localization pattern of the electron density in the highest occupied molecular orbital emerged as a useful indicator of the relative affinity of tryptamines for the LSD/serotonin receptor. These conclusions support the use of judiciously chosen molecular reactivity criteria for the prediction of biological potency of drugs in this series.

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ACKNOWLEDGMENTS The computations were supported in part by a grant of computer time from the University Computer Center of the City University of New York. Analysis of results in this work was carried out in part on the PROPHET System, a national computer resource sponsored by the NIH through the Chemical/Biological Information-Handling Program, Division of Research.