INHIBITION OF [H-3] PAROXETINE BINDING BY VARIOUS SEROTONIN UPTAKE INHIBITORS - STRUCTURE-ACTIVITY-RELATIONSHIPS

Fifty-four compounds structurally related to zimeldine or alaproclate and eight reference substances were examined as inhibitors of the high affinity binding of [H-3]paroxetine to rat cerebral cortical membranes as a measure of the affinity of the 5-hydroxytryptamine (5-HT) transporter. None of the compounds had an affinity as high as paroxetine (K(D) = 0.026 nM). The most potent compound, 3-(4-methoxyphenyl)-l-methyl-3-phenylpropylamine (2) had a 5 times lower affinity than paroxetine. Some other diphenyl-1-methyl-propylamines displayed high affinity, e.g. the 4-bromo (4) and 2-bromo (7) derivatives. The primary amine analogue of zimeldine substituted with an alpha-methyl group (19) had an affinity only slightly less than that of norzimeldine (11) but an almost 100 times higher affinity than that of the unsubstituted primary zimeldine analogue (57). These observations indicate that a methyl group on the alpha-carbon and on the nitrogen both increase the affinity for the [H-3] paroxetine binding site. The structure activity relationship for the compounds to inhibit [H-3]paroxetine binding was highly significantly correlated to the inhibition of 5-HT uptake in mouse brain slices (P < 0.01) and to the inhibition of noradrenaline uptake in the same slices (P < 0.05). QSAR analysis of the zimeldine series of compounds indicates that substitution of halogens of the 2-position of the phenyl ring is unfavourable. The cis configuration promotes higher activity than the trans configuration.