Further evaluation of the tropane analogs of haloperidol

Bioorg Med Chem Lett. 2014 Sep 1;24(17):4294-7. doi: 10.1016/j.bmcl.2014.07.018. Epub 2014 Jul 14.


Previous work from our labs has indicated that a tropane analog of haloperidol with potent D2 binding but designed to avoid the formation of MPP(+)-like metabolites, such as 4-(4-chlorophenyl)-1-(4-(4-fluorophenyl)-4-oxobutyl)pyridin-1-ium (BCPP(+)) still produced catalepsy, suggesting a strong role for the D2 receptor in the production of catalepsy in rats, and hence EPS in humans. This study tested the hypothesis that further modifications of the tropane analog to produce compounds with less potent binding to the D2 receptor than haloperidol, would produce less catalepsy. These tests have now revealed that while haloperidol produced maximum catalepsy, these compounds produced moderate to low levels of catalepsy. Compound 9, with the least binding affinity to the D2R, produced the least catalepsy and highest Minimum Adverse Effective Dose (MAED) of the analogs tested regardless of their affinities at other receptors including the 5-HT1AR. These observations support the hypothesis that moderation of the D2 binding of the tropane analogs could reduce catalepsy potential in rats and consequently EPS in man.

Keywords: Antipsychotic agents; Catalepsy; Haloperidol; Pyridinium metabolite; Tropane analogs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antipsychotic Agents / adverse effects
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacology*
  • Apomorphine
  • Catalepsy / chemically induced
  • Dose-Response Relationship, Drug
  • Haloperidol / adverse effects
  • Haloperidol / analogs & derivatives*
  • Haloperidol / chemistry
  • Haloperidol / pharmacology*
  • Mice
  • Molecular Structure
  • Motor Activity / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / metabolism*
  • Structure-Activity Relationship
  • Tropanes / adverse effects
  • Tropanes / chemistry*


  • Antipsychotic Agents
  • Receptors, Dopamine D2
  • Tropanes
  • Haloperidol
  • Apomorphine