INHIBITION OF NEURONAL UPTAKE OF BIOGENIC-H-3 AMINES INTO RAT CEREBRAL-CORTEX BY PARTIALLY AND FULLY SATURATED DERIVATIVES OF IMIPRAMINE AND DESIPRAMINE .3. IMPORTANCE OF THE AROMATIC RING IN ADRENERGIC AMINES

In order to assess the importance of the aromatic rings in inhibition of neuronal amine uptake produced by tricyclic antidepressant drugs, derivatives of imipramine (IMI) and dcsipramine (DMI) were prepared in which either one (IMIH, DMIH) or both (IMIH2, DMIH2) of the aromatic rings were fully reduced to cyclohexane rings. The relative abilities of these compounds to inhibit the uptake of l-[3H]-norepinephrine (NE), [3H]-dopamine (DA) and [3H]-5-hydroxytryptamine (5-HT) into chopped tissue of rat cerebral cortex were determined. Reduction of one or both aromatic rings did not alter significantly the inhibition of uptake of [3H]-DA or [3H]5-HT produced by either IMI or DMI (IC50 values 25-80 μM). However, saturation of one or both rings abolished the selectivitv of DMI for inhibition of NE uptake (IC50 0.12 μM). decreasing potency 150-fold (IC50 18.3 μM) and 250-fold (IC50 29.4 μM) respectively. The effect of aromatic ring reduction on the IMI-induced inhibition of NE uptake was much less pronounced. The results suggest that hydrophobic rather than π-electron attractive forces are involved in the interaction of DMI or IMI with DA or 5-HT uptake sites. However, the loss in selectivity for inhibition of NE uptake upon reduction of DMI may reflect loss of π-electron interactions in the binding of DMI to the NE uptake site, or may reflect increased sensitivity to spatial disposition of the hydrophobic binding areas of the drug relative to that found at the DA or 5-HT amine uptake sites. © 1979.