BINDING POTENCY OF 6-NITROQUIPAZINE ANALOGS FOR THE 5-HYDROXYTRYPTAMINE REUPTAKE COMPLEX

The in-vitro inhibition constants (K-i) of nine structural analogues of the potent 5-hydroxytryptamine (5-HT)-uptake inhibitor, 6-nitroquipazine, were determined to assess the structure-affinity relationship of these derivatives. The goal of these studies was to determine those positions on 6-nitroquipazine that could be derivatized without significantly decreasing the affinity of the drug for the binding site, so that radiolabels such as I-123, Br-76 or F-18 might be appended for in-vivo imaging studies of the 5-HT reuptake system. Using bromine as a steric probe, the rank order of potency of bromine-substituted 6-nitroquipazine analogues for inhibiting the binding of [H-3]paroxetine to the 5-HT reuptake binding site was: 8-<3-<7-<4-<5-bromo. The in-vitro equipotent molar ratio (EPMR, K-i (analogue)/K-i(6-nitroquipazine)) of the 5-bromo analogue was 0.57, indicating that this analogue had greater affinity for the 5-HT reuptake complex than 6-nitroquipazine. Derivatization at the 5-position with fluorine and iodine also resulted in potent compounds with EPMR values of 1.1 and 0.83, respectively. Substitution of quipazine with bromo, cyano, and formyl groups at the 6-position produced less potent compounds than the 6-nitro group. Based upon the high affinities of the 5-bromo-, 5-fluoro- and 5-iodo-6-nitroquipazines for the 5-HT reuptake complex, these compounds are candidates for radiolabelling for in-vivo studies of the 5-HT reuptake site.