Abstract

The relative potencies for inhibition of norepinephrine uptake for a series of primary amine, secondary methylamine and tertiary dimethylamine derivatives of monophenyl and diphenyl analogs of desmethylimipramine and protriptyline have been determined. The order of potency of these agents as inhibitors of uptake of norepinephrine into cortical synaptosomes and into adrenergic nerves of rabbit aorta was tricyclic > diphenyl > monophenyl. In addition, the octanol-water partition coefficients at pH 7.4 (P_a) were estimated for the compounds. P_a was found generally to decrease in the order tricyclic, diphenyl monophenyl. Correlation coefficients for the relationship between log P_a and log relative potency of these compounds. including data for a carhazole derivative and iprindole, indicated that while the lipophilicity of the aromatic "end" of the molecule was of some importance in determining potency, this importance was heavily modulated by the three dimensional display of the hydrophobic groups present. Furthermore, it was noted that although the secondary methylamine tricyclic compounds were considerably more potent than their primary and tertiary dimethylamine derivatives, the secondary methylamine diphenyl and monophenyl compounds were not considerably more potent than their primary or tertiary dimethylamine derivatives. In this regard it was noted. from molecular models, that. the 2-carbon bridge which "fixes" the orientation of the two phenyl rings in tricyclic compounds also fixes the orientation of both the C or N between the two rings and the first C of the alkylamine chain. It was concluded that this orientation helped to align the whole chain so that the single methyl group attached to the terminal nitrogen made a "lock and key" fit with an ancillary hydrophobic binding site.