CONFORMATIONALLY RESTRICTED ANALOGS OF REMOXIPRIDE AS POTENTIAL ANTIPSYCHOTIC AGENTS

Several conformationally restricted derivatives of thyl-2-pyrrolidinyl )methyl)-2,6-dimethoxybenzamide (remoxipride) were synthesized and eva luated in vitro for their ability to inhibit [H-3]raclopride binding a t the dopamine D-2 receptor. The cyclic benzamides designed to mimic t he intramolecular hydrogen bonding of desmethylremoxipride (4, FLA-797 ) included 2,3-dihydro-4H-1,3-benzoxazin-4-ones, 2,3-dihydro-4H-1,3-be nzthiazin-4-ones, phthalimides, 1-isoindolinones, 1,2-benzisothiazol-3 (2H)-ones, and 1,2-benzisothiazol-3(2H)-one 1,1-dioxides. In this seri es, enhanced affinities to the dopamine D-2 receptor were not observed . The phthalimidine analogue 24b -6-chloro-2-(1-ethylpyrrolidinyl)-l-i soindolinone) exhibited the highest affinity to the dopamine D-2 recep tor with an IC50 of 1.3 muM, which was equipotent to remoxipride.