Potential antipsychotic agents. 7. Synthesis and antidopaminergic properties of the atypical highly potent (S)-5-bromo-2,3-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide and related compounds. A comparative study

J Med Chem. 1990 Aug;33(8):2305-9. doi: 10.1021/jm00170a040.


(S)-5-Bromo-2,3-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide (6) and some related compounds, i.e. the R isomer 7, the 3-hydroxy analogue 8, the desbromo derivative 9, the monomethoxy compound 10, and the 2,4-dimethoxy analogue 11, have been synthesized from the corresponding benzoic acids. The benzamides, lacking o-hydroxy groups, were evaluated for their affinity for the [3H]spiperone binding site and for their inhibition of apomorphine-induced behavioral responses in relation to the effect of the corresponding salicylamides. Besides the 2-hydroxy-3-methoxybenzamide 12 and the related 1,4-benzodioxane (13) and 2,3-dihydrobenzofuran (14), carboxamides were investigated in order to evaluate the stereoelectronic requirements on the 2-methoxy group for the receptor interaction. The study supports the view that the o-methoxy group may adopt coplanar, as well as perpendicular orientations, and maintain the intramolecular hydrogen bonding required in the bioactive conformation. The benzamide 6 was found to be equipotent with the analogous highly active salicylamide 3 (FLB 463) both in vitro and in vivo. In addition, 6 displayed a preferential inhibition of the hyperactivity component of the behavioral syndrome, which is regarded to indicate a low tendency to induce extrapyramidal side effects in man at antipsychotically effective doses. The benzamide class of compounds (6-10) were found to be somewhat more sensitive to the structural modifications than the salicylamide class, i.e. the o-hydroxy-substituted benzamides (2-5). The potent and selective benzamide 6 (FLB 457) is highly suitable for investigations of dopamine D-2 mediated responses and, in radiolabeled form, for receptor binding studies in vitro and in vivo.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antipsychotic Agents / chemical synthesis*
  • Antipsychotic Agents / pharmacology
  • Apomorphine / pharmacology
  • Behavior, Animal / drug effects
  • Benzamides / chemical synthesis*
  • Benzamides / metabolism
  • Benzamides / pharmacology
  • Chemical Phenomena
  • Chemistry
  • Corpus Striatum / metabolism
  • Dopamine Antagonists*
  • Hydrogen Bonding
  • Male
  • Molecular Structure
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / metabolism
  • Pyrrolidines / pharmacology
  • Rats
  • Rats, Inbred Strains
  • Receptors, Dopamine / drug effects
  • Receptors, Dopamine / metabolism
  • Receptors, Dopamine D2
  • Remoxipride
  • Salicylamides / chemical synthesis
  • Salicylamides / metabolism
  • Salicylamides / pharmacology
  • Spiperone / metabolism
  • Structure-Activity Relationship


  • Antipsychotic Agents
  • Benzamides
  • Dopamine Antagonists
  • Pyrrolidines
  • Receptors, Dopamine
  • Receptors, Dopamine D2
  • Salicylamides
  • Remoxipride
  • FLB 457
  • Spiperone
  • Apomorphine