Effect of N-alkylation on the affinities of analogues of spiperone for dopamine D2 and serotonin 5-HT2 receptors

J Med Chem. 1992 Feb 7;35(3):423-30. doi: 10.1021/jm00081a002.


Two series of N-substituted spiperone analogues were prepared and evaluated in vitro to measure their affinities for dopamine D2 and serotonin 5-HT2 receptors. Substitution of the amide nitrogen with an alkyl group of five carbon units or less resulted in analogues displaying a low selectivity for D2 compared to 5-HT2 receptors. However, a moderate improvement in selectivity for D2 receptors was observed with N-benzylspiperone. Substitution at either the ortho or para position of the benzyl group resulted in a further reduction in affinity for 5-HT2 receptors and improvement in the selectivity ratio. Examination of N-substituted analogues of spiperone may provide insights into the topography of the antagonist binding region of the 5-HT2 receptor. The results also suggest that an 18F-labeled analogue of N-(4-nitrobenzyl)spiperone (4p) may be a suitable tracer for studying D2 receptors with positron emission tomography since this compound displays a high selectivity for D2 receptors relative to that of spiperone and N-methylspiperone.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkylation
  • Receptors, Dopamine / metabolism*
  • Receptors, Dopamine D2
  • Receptors, Serotonin / metabolism*
  • Spiperone / analogs & derivatives*
  • Spiperone / metabolism
  • Structure-Activity Relationship


  • Receptors, Dopamine
  • Receptors, Dopamine D2
  • Receptors, Serotonin
  • Spiperone