Binding potency of paroxetine analogues for the 5-hydroxytryptamine uptake complex

The in-vitro inhibition constants (Ki) of 14 structural analogues of the potent 5-hydroxytryptamine (5-HT)-uptake inhibitor paroxetine were determined to assess the structure-affinity relationship of these derivatives. A goal of these studies was to determine those positions on paroxetine which could be derivatized without significantly decreasing the affinity of the drug for the binding site, so that radiolabels such as [18F]fluoroalkyl groups might be appended for future in-vivo imaging studies of the 5-HT uptake system. Using the methyl moiety as a steric probe for these studies, it was found that the rank order of potency of various methyl-substituted paroxetine analogues for inhibiting the binding of [3H]paroxetine to the 5-HT re-uptake site was: 4'-approximately equal to 3'-approximately equal to 2''- > 2'-approximately equal to 1- > 5''- > 6''-methyl. The in-vitro equipotent molar ratios (EPMR, Ki(analogue)/Ki(paroxetine)) of the analogues were determined, and the EPMRs of the 4'-, 3'-, and 2''-methyl derivatives were 1.9, 2.2 and 2.2, respectively. The 4'- and 2''-fluoromethyl and -fluoroethyl analogues were synthesized, and the EPMRs of the 4'- and 2''-fluoromethyl derivatives were determined to be 2.0 and 3.5, and those of the 4'- and 2''-fluoroethyl analogues were 5.2 and 6.2, respectively. The 2''-fluoromethyl analogue was unstable in aqueous solutions, and it is not a promising ligand for in-vivo studies.(ABSTRACT TRUNCATED AT 250 WORDS)