CONFORMATIONALLY RESTRICTED ANALOGS OF REMOXIPRIDE AS POTENTIAL ANTIPSYCHOTIC AGENTS

Several conformationally restricted derivatives of (S)-3-bromo-N-((1-ethyl-2-pyrrolidinyl)methyl)-2,6-dimethoxybenzamide (remoxipride) were synthesized and evaluated in vitro for their ability to inhibit [H-3]raclopride binding at the dopamine D-2 receptor. The cyclic benzamides designed to mimic the intramolecular hydrogen bonding of desmethylremoxipride (4, FLA-797) included 2,3-dihydro-4H-1,3-benzoxazin-4-ones, 2,3-dihydro-4H-1,3-benzthiazin-4-ones, phthalimides, 1-isoindolinones, 1,2-benzisothiazol-3(2H)-ones, and 1,2-benzisothiazol-3(2H)-one 1,1-dioxides. In this series, enhanced affinities to the dopamine D-2 receptor were not observed. The phthalimidine analogue 24b ((S)-6-chloro-2-(1-ethylpyrrolidinyl)-l-isoindolinone) exhibited the highest affinity to the dopamine D-2 receptor with an IC50 of 1.3 muM, which was equipotent to remoxipride.