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

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

Laboratório de Psicofarmacologia Experimental, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Bioorganic & medicinal chemistry 2010 Mar 1

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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. Copyright 2010 Elsevier Ltd. All rights reserved.

Citation

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. Searching for multi-target antipsychotics: Discovery of orally active heterocyclic N-phenylpiperazine ligands of D2-like and 5-HT1A receptors. Bioorganic & medicinal chemistry. 2010 Mar 1;18(5):1925-35