Conformationally restricted analogues 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 [3H]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)-1-isoindolinone) exhibited the highest affinity to the dopamine D-2 receptor with an IC50 of 1.3 microM, which was equipotent to remoxipride.
Norman
M H
MH
Division of Organic Chemistry, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.
Kelley
J L
JL
Hollingsworth
E B
EB
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D008297:Male; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D017330:Remoxipride / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D001549:Benzamides; D017448:Receptors, Dopamine D2; D017330:Remoxipride