Abstract

Relative potencies for tricyclic antidepressants and related compounds as inhibitors of the uptake of norepinephrine have been asseased. Molecular models reveal that high potency occurs in tricyclics in which the phenyls are at appreciable angles to one another (dihydrodibenzazepine, phenothiazine, dibenzocycloheptadiene, dibenzocycloheptatriene) and moderate potency occurs in tricycics in which the phenyls are at slight angles (phenozaxine) as well as in an unbridged diphenyl system (diphenylmethylidene). Tricyclics in which the phenyl rings are in the same plane (carbazole) or nearly so (phenanthridone, dihydrophenanthridine) are weakly active. All ring systems, whether of high, moderate or weak activity, vary in potency with the methylation of the terminal nitrogen (N) such that 2° amine >> 3° amine ≅ 1°. High potency occurs with the 2° methylamine but not with the 2° ethylamine or isopropylamine. Compounds studied have >90% of the terminal N protonated at pH 7.4 and so are positively charged. The 4° N derivatives are moderately potent. Thus, the charged form of the inhibitors is probably the active species. The kinetics for the uptake of norepinephrine by aortic strips in the presence and absence of the inhibitors indicates that both substances compete for the same active site in the adrenergic nerve membrane. If the assumption is made that this site is best fit by the extended conformation of phenethylamine, many structure-activity relationships are rationalized.