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Molecular Pharmacology, Vol 14, 596-606, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

On the Topology of the Norepinephrine Transport Carrier in Rat Hypothalamus

The Site of Action of Tricyclic Uptake Inhibitors

TOMAS DE PAULIS 1, DIANA KELDER 1, SVANTE B. ROSS 1, and NILS E. STJERNSTRÖM 2

1 Research and Development Laboratories, Astra Läkemedel AB, S-151 85 Södertälje, Sweden
2 Astra Pharmaceuticals, S-151 85 Södertälje, Sweden

The conformations of 31 rigid and semirigid compounds structurally related to the tricyclic antidepressant agents have been correlated with their inhibitory activities toward the uptake of norepinephrine in synaptosomes of rat hypothalamus. A relationship was found, in terms of four intramolecular distances, between the potencies of these compounds and their structural similarities to the most potent compound, N,N-dimethylspiro[5H-dibenzo[a,d]cycloheptene-5,1'-cyclohexane]-4-amine (A 1866). The stereochemical parameters were selected to describe the position of the nitrogen atom in relation to the centers of the two aromatic nuclei. It is suggested that the competitive antagonistic behavior of the tricycic compounds is independent of their structural similarities to either the gauche or the anti conformation of norepinephrine. It is concluded that the norepinephrine transport carrier is equipped with active sites displaying two different topologies. One is complementary to the structure of A 1866, for which the tricyclic antidepressant agents have affinity; the other has a topology complementary to the structure of norepinephrine, to which the catecholamines and some phenylalkylamine derivatives fit.

Note:
ACKNOWLEDGMENT We thank Dr. Brian Pring for linguistic revision of the manuscript.

Submitted on October 21, 1977
Accepted on February 8, 1978




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