KINETIC AND THERMODYNAMIC CONSIDERATIONS REGARDING THE INHIBITION BY TRICYCLIC ANTIDEPRESSANTS OF THE UPTAKE OF TRITIATED NOREPINEPHRINE BY THE ADRENERGIC NERVES IN RABBIT AORTIC STRIPS

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

K₄ values have been determined for desmethylimipramine (A), imipramine (B) and their primary amine derivative (C), as well as for nortriptyline (D). The kinetic plots were made over the norepinephrine range 6 x 10^-7 M to 6 x 10^-6 M. This range encompasses the major portion of the steep part of the concentration-uptake curve. From K₄ values, desmethylimipramine is approximately 10 times more potent than B or C and is equipotent with D. The difference in F° (difference in total free energy of binding) values observed when desmethylimipramine (a secondary methylamine) and its primary amine derivative C were used as inhibitors, is very close to the theoretical F° difference which would result if a "lock and key" fit of the N-methyl of desmethylimipramine were made with an apolar area of the pumping system. It was noted that the double reciprocal plot describing the inhibition of norepinephrine uptake by A deviates sharply from a straight line at concentrations between 4 x 10^-7 M and 10^-7 M. At 10^-7 M norepinephrine, A is not10 times more potent but approximately 100 times more potent than C or B. Plots for B, C or D do not deviate at low norepinephrine concentrations. The deviation with A is attributed to a relatively small effect at a second site in the uptake mechanism. Since the ED50 for contraction of the aortic strips is 10^-7 M, and since the rate of uptake at this concentration is very small, the effects of such a second small inhibitory action of A may be of considerable practical consequence.