Searching for multi-target antipsychotics: Discovery of orally active heterocyclic N-phenylpiperazine ligands of D2-like and 5-HT1A receptors.
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.
Neves
Gilda
G
Laboratório de Psicofarmacologia Experimental, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Menegatti
Ricardo
R
Antonio
Camila B
CB
Grazziottin
Luiza R
LR
Vieira
Renan O
RO
Rates
Stela M K
SM
Noël
François
F
Barreiro
Eliezer J
EJ
Fraga
Carlos A M
CA
D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D002460:Cell Line; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy
C549977:1-((1-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-phenylpiperazine; D014150:Antipsychotic Agents; C518328:LASSBio-579; D008024:Ligands; D010879:Piperazines; D011720:Pyrazoles; D017448:Receptors, Dopamine D2; D044282:Receptor, Serotonin, 5-HT1A; C031503:phenylpiperazine