CONFORMATIONAL SIMILARITIES BETWEEN MOLECULAR MODELS OF PHENETHYLAMINE AND OF POTENT INHIBITORS OF THE UPTAKE OF TRITIATED NOREPINEPHRINE BY ADRENERGIC NERVES IN RABBIT AORTA

¹ Departments of Pharmacology, Wellcome Research Laboratories, Burroughs Wellcome & Co. (U.S.A.) Inc., Tuckahoe, New York, University of Vermont School of Medicine, Burlington, Vermont and Laboratories of Medicinal Chemistry, College of Pharmaceutical Sciences, Columbia University, New York, New York

Tricycic antidepressants, deoxypipradrol, methylphenidate and cocaine are competitive inhibitors of the uptake of norepinephrine by rabbit aortic strips. All have pK_a. values greater than 8.5 and, therefore, are greater than 90% protonated and positively charged at physiologic pH. These agents can readily take conformations such that one phenyl ring and the protonated nitrogen superimpose over their counterparts in the planar, trans-staggered conformation of -phenethylamine. In these conformations the inhibitors have a second phenyl ring or a carbomethoxy group extending above the plane of the phenethylamine in the vicinity of the -carbon of the phenethylamine. Tricyclic antidepressants, cocaine, methylphenidate and deoxypipradrol bear adequate similarities to each other and to -phenethylamine in regard to pK_a, kinetics, structure and conformational possibilities to indicate that they attach to the same "amine pump" receptor site as does norepinephrine. The relative potencies of these agents as inhibitors of uptake of tritiated norepinephrine into rabbit aortic strips have been determined. These agents have sufficient structural and conformational differences to permit a rationale to be developed which explains their differences in potency as inhibitors of the uptake of norepinephrine.

This article has been cited by other articles:

				Z. Sun, D. J. Murry, S. P. Sanghani, W. I. Davis, N. Y. Kedishvili, Q. Zou, T. D. Hurley, and W. F. Bosron Methylphenidate Is Stereoselectively Hydrolyzed by Human Carboxylesterase CES1A1 J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 469 - 476. [Abstract] [Full Text] [PDF]