CONCERNING THE MOLECULAR REQUIREMENTS FOR THE INHIBITION OF THE UPTAKE OF RACEMIC ³H-NOREPINEPHRINE INTO RAT CEREBRAL CORTEX SLICES BY TRICYCLIC ANTIDEPRESSANTS AND RELATED COMPOUNDS

¹ Department of Pharmacology, The Wellcome Research Laboratories, Burroughs Wellcome Company, Inc., Research Triangle Park, North Carolina

The relative potencies of tricycics and related compounds as inhibitors of the uptake of ³H-norepinephrine into rat cerebral cortex have been determined. Kinetic studies indicate that these compounds competitively inhibit the uptake of ³H-norepinephrine in the rat cortex. Greatest inhibition of uptake into the cortical slices has been found with compounds in which the phenyl rings are at fixed angles to an another (not coplanar) (dihydro dibenzazepine, dibenzocycloheptadiene and dibenzocycloheptatriene). Weak inhibition occurs with compounds which have coplanar phenyl rings (carbazole). Intermediate potency is observed when the phenyl rings are unbridged (diphenylmethylidene). These findings are in general agreement with those reported by Maxwell et al. (J. Pharxnacol. Exp. Ther. 166: 320-329, 1969) for the rabbit aortic strip. In the cortex slices as in the aorta the primary amine and the tertiary dimethylamine derivatives are equipotent in the series where inhibition is marked. The secondary methylamines of the dihydrodibenzazepine, dibenzocyclo heptadiene and the diphenylmethylidene series showed greater potency than their respective primary or teritary derivatives. However, in the dibenzocycloheptatriene series all three derivatives are equipotent. This is in distinction to the aorta in which, in all the series except the carbasole series, the secondary methylamines are considerably more potent than the primary and tertiary amines. It is postulated that in the brain cortex the hydrophobic area of the "amine pump" receptor receiving the N-methyls distinguishes between minor differences in the presentation of these N-methyl groups. This is not the case in the aorta. The membrane amine pump mechanisms in rabbit aorta and rat cerebral cortex appear to have fundamentally similar properties but differ in at least one respect.