Moderate chemical modifications of WAY-100635 improve the selectivity for 5-HT1A versus D4 receptors

Bioorg Med Chem Lett. 2012 Jul 15;22(14):4550-4. doi: 10.1016/j.bmcl.2012.05.119. Epub 2012 Jun 7.

Abstract

The selectivity for 5-HT(1A) versus D(4) receptors is significantly increased when the basic side chain of WAY-100635 is replaced by a 4-phenylpiperazine (3e) or a 4-phenyl-1,2,3,6-tetrahydropyridine moiety (3i). The 4-phenyl-1,2,3,6-tetrahydropyridine compounds (3i-l) have a higher affinity for 5-HT(1A) receptors than do the corresponding unsubstituted phenylpiperazine analogues (3e-h). Compounds 3e and 3i appear to be selective for 5-HT(1A) receptors over other relevant receptors and still behave as neutral antagonists.

Publication types

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

MeSH terms

  • Molecular Structure
  • Piperazines / chemistry*
  • Piperazines / pharmacology
  • Pyridines / chemistry*
  • Pyridines / pharmacology
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptors, Dopamine D4 / antagonists & inhibitors*
  • Receptors, Dopamine D4 / metabolism
  • Serotonin 5-HT1 Receptor Antagonists / chemistry*
  • Serotonin 5-HT1 Receptor Antagonists / pharmacology
  • Structure-Activity Relationship

Substances

  • Piperazines
  • Pyridines
  • Serotonin 5-HT1 Receptor Antagonists
  • Receptor, Serotonin, 5-HT1A
  • Receptors, Dopamine D4
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide