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

The in-vitro inhibition constants (K-i) of nine structural analogues o f the potent 5-hydroxytryptamine (5-HT)-uptake inhibitor, 6-nitroquipa zine, were determined to assess the structure-affinity relationship of these derivatives. The goal of these studies was to determine those p ositions on 6-nitroquipazine that could be derivatized without signifi cantly decreasing the affinity of the drug for the binding site, so th at radiolabels such as I-123, Br-76 or F-18 might be appended for in-v ivo imaging studies of the 5-HT reuptake system. Using bromine as a st eric probe, the rank order of potency of bromine-substituted 6-nitroqu ipazine 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 equ ipotent molar ratio (EPMR, K-i (analogue)/K-i(6-nitroquipazine)) of th e 5-bromo analogue was 0.57, indicating that this analogue had greater affinity for the 5-HT reuptake complex than 6-nitroquipazine. Derivat ization at the 5-position with fluorine and iodine also resulted in po tent compounds with EPMR values of 1.1 and 0.83, respectively. Substit ution of quipazine with bromo, cyano, and formyl groups at the 6-posit ion produced less potent compounds than the 6-nitro group. Based upon the high affinities of the 5-bromo-, 5-fluoro- and 5-iodo-6-nitroquipa zines for the 5-HT reuptake complex, these compounds are candidates fo r radiolabelling for in-vivo studies of the 5-HT reuptake site.