Potential antipsychotic agents. 9. Synthesis and stereoselective dopamine D-2 receptor blockade of a potent class of substituted (R)-N-[(1-benzyl-2-pyrrolidinyl)methyl]benzamides. Relations to other side chain congeners

J Med Chem. 1991 Mar;34(3):948-55. doi: 10.1021/jm00107a012.


A number of substituted N-[(1-benzyl-2-pyrrolidinyl)methyl]benzamides and -salicylamides have been prepared and investigated as dopamine D-2 receptor antagonists in vitro and in vivo. The affinity was found to be confined to the R enantiomer, in contrast to the corresponding N-ethyl or N-allyl derivatives. The X-ray structure of one of the compounds (15) confirmed the R stereochemistry. This compound (15) was found to adopt a solid-state conformation in which the 4-fluorobenzyl group is folded over the salicylamide moiety. Benzamides having a 2,3-dimethoxy substitution pattern (24 and 26) or salicylamides with a 5,6-dimethoxy grouping (21 and 22) were especially potent, in that they inhibited [3H]spiperone binding to rat striatal dopamine D-2 receptors in vitro with IC50 values of about 1 nM. The new compounds' ability to block apomorphine-induced stereotypies correlated with the affinity for the [3H]spiperone binding site. Higher dose levels were necessary to induce catalepsy than to block the apomorphine-induced responses. The influence of the aromatic substituents on the potency of substituted benzamides with three types of side chains, i.e. (R)-(1-benzyl-2-pyrrolidinyl)methyl, (S)-(1-ethyl-2-pyrrolidinyl)methyl and 1-benzyl-4-piperidinyl, was compared. The 3-bromo-5,6-dimethoxysalicylamide substitution pattern was found to be the most general since it gave very potent compounds in all series. The substituted (R)-N-[(1-(4-fluoro-benzyl)-2-pyrrolidinyl)methyl]benzamides (26) and -salicylamides (22) are suitable for development into 18F radioligands without altering the parent structure.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antipsychotic Agents / chemical synthesis*
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacology
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Benzyl Compounds / chemical synthesis
  • Benzyl Compounds / chemistry
  • Benzyl Compounds / pharmacology
  • Chemical Phenomena
  • Chemistry
  • Corpus Striatum / metabolism
  • Dopamine Antagonists*
  • Male
  • Molecular Conformation
  • Molecular Structure
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology
  • Raclopride
  • Rats
  • Rats, Inbred Strains
  • Receptors, Dopamine / metabolism
  • Receptors, Dopamine D2
  • Salicylamides / chemical synthesis*
  • Salicylamides / chemistry
  • Salicylamides / metabolism
  • Salicylamides / pharmacology
  • Spiperone / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • X-Ray Diffraction


  • Antipsychotic Agents
  • Benzamides
  • Benzyl Compounds
  • Dopamine Antagonists
  • Pyrrolidines
  • Receptors, Dopamine
  • Receptors, Dopamine D2
  • Salicylamides
  • Raclopride
  • Spiperone