Searching for multi-target antipsychotics: Discovery of orally active heterocyclic N-phenylpiperazine ligands of D2-like and 5-HT1A receptors.

Abstract

We described herein the design, synthesis, and pharmacological evaluation of N-phenylpiperazine heterocyclic derivatives as multi-target compounds potentially useful for the treatment of schizophrenia. The isosteric replacement of the heterocyclic ring at the biaryl motif generating pyrazole, 1,2,3-triazole, and 2-methylimidazole[1,2-a]pyridine derivatives resulted in 21 analogues with different substitutions at the para-biaryl and para-phenylpiperazine positions. Among the compounds prepared, 4 (LASSBio-579) and 10 (LASSBio-664) exhibited an adequate binding profile and a potential for schizophrenia positive symptoms treatment without cataleptogenic effects. Structural features of this molecular scaffold are discussed regarding binding affinity and selectivity for D(2)-like, 5-HT(1A), and 5-HT(2A) receptors.

• Authors: Gilda Neves, Ricardo Menegatti, Camila B Antonio, Luiza R Grazziottin, Renan O Vieira, Stela M K Rates, François Noël, Eliezer J Barreiro, Carlos A M Fraga
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 18 Issue 5 Pg. 1925-35 (Mar 01 2010) ISSN: 1464-3391 [Electronic] England
• PMID: 20153652 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Ltd. All rights reserved.

Chemical References

• 1-((1-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-phenylpiperazine
• Antipsychotic Agents
• LASSBio-579
• Ligands
• Piperazines
• Pyrazoles
• Receptors, Dopamine D2
• Receptor, Serotonin, 5-HT1A
• phenylpiperazine

Topics

• Administration, Oral
• Animals
• Antipsychotic Agents (chemical synthesis, chemistry, therapeutic use)
• Cell Line
• Humans
• Ligands
• Male
• Mice
• Piperazines (chemical synthesis, chemistry, therapeutic use)
• Pyrazoles (chemical synthesis, chemistry, therapeutic use)
• Rats
• Receptor, Serotonin, 5-HT1A (metabolism)
• Receptors, Dopamine D2 (metabolism)
• Schizophrenia (drug therapy)