title: Synthesis and pharmacological evaluation of new N-phenylpiperazine derivatives designed as homologues of the antipsychotic lead compound LASSBio-579.
abstract: In an attempt to increase the affinity of our antipsychotic lead compound LASSBio-579 (1-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)methyl)-4-phenylpiperazine; (2)) for the 5-HT(2A) receptor, we synthesized five new N-phenylpiperazine derivatives using a linear synthetic route and the homologation strategy. The binding profile of these compounds was evaluated for a series of dopaminergic, serotonergic and alpha-adrenergic receptors relevant for schizophrenia, using classical competition assays. Increasing the length of the spacer between the functional groups of (2) proved to be appropriated since the affinity of these compounds increased 3-10-fold for the 5-HT(2A) receptor, with no relevant change in the affinity for the D₂-like and 5-HT(1A) receptors. A GTP-shift assay also indicated that the most promising derivative (1-(4-(1-(4-chlorophenyl)-1H-pyrazol-4-yl) butyl)-4-phenylpiperazine) (LASSBio-1635) (6) has the expected efficacy at the 5-HT(2A) receptors, acting as an antagonist. Intraperitoneal administration of (6) prevented apomorphine-induced climbing behavior and ketamine-induced hyperlocomotion in mice, in a dose dependent manner. Together, these results show that (6) could be considered as a new antipsychotic lead compound.
authors.affiliation: Laboratório de Farmacologia Bioquímica e Molecular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, 373, Sala J1-17, CEP 21941-912 Ilha do Fundão, Rio de Janeiro, Brazil.
authors.forename: Thais E T
authors.initials: TE
authors.lastname: Pompeu
authors.forename: Fernando R S
authors.initials: FR
authors.lastname: Alves
authors.forename: Carolina D M
authors.initials: CD
authors.lastname: Figueiredo
authors.forename: Camila B
authors.initials: CB
authors.lastname: Antonio
authors.forename: Vivian
authors.initials: V
authors.lastname: Herzfeldt
authors.forename: Bruna C
authors.initials: BC
authors.lastname: Moura
authors.forename: Stela M K
authors.initials: SM
authors.lastname: Rates
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: Carlos A M
authors.initials: CA
authors.lastname: Fraga
authors.forename: François
authors.initials: F
authors.lastname: Noël
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology
chemical_list: D014150:Antipsychotic Agents; C518328:LASSBio-579; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; C031503:phenylpiperazine
keywords: 5-HT(2A); Antipsychotics; Homologation; LASSBio-579; N-Phenylpiperazine; Schizophrenia