title: LASSBio-1422: a new molecular scaffold with efficacy in animal models of schizophrenia and disorders of attention and cognition.
abstract: Aiming to identify new antipsychotic lead-compounds, our group has been working on the design and synthesis of new N-phenylpiperazine derivatives. Here, we characterized LASSBio-1422 as a pharmacological prototype of this chemical series. Adult male Wistar rats and CF1 mice were used for in-vitro and in-vivo assays, respectively. LASSBio-1422 [1 and 5 mg/kg, postoperatively (p.o.)] inhibited apomorphine-induced climbing as well as ketamine-induced hyperlocomotion (1 and 5 mg/kg, p.o.), animal models predictive of efficacy on positive symptoms. Furthermore, LASSBio-1422 (5 mg/kg, p.o.) prevented the prepulse impairment induced by apomorphine, (±)-2,5-dimethoxy-4-iodoamphetamine, and ketamine, as well as the memory impairment induced by ketamine in the novel object-recognition task at the acquisition, consolidation, and retrieval phases of memory formation. Potential extrapyramidal side-effects and sedation were assessed by catatonia, rota-rod, locomotion, and barbiturate sleeping time, and LASSBio-1422 (15 mg/kg, p.o.) did not affect any of the parameters observed. Binding assays showed that LASSBio-1422 has a binding profile different from the known atypical antipsychotic drugs: it does not bind to AMPA, kainate, N-methyl-D-aspartate, glicine, and mGluR2 receptors and has low or negligible affinity for D1, D2, and 5-HT2A/C receptors, but high affinity for D4 receptors (Ki=0.076 µmol/l) and, to a lesser extent, for 5-HT1A receptors (Ki=0.493 µmol/l). The antagonist action of LASSBio-1422 at D4 receptors was assessed through the classical GTP-shift assay. In conclusion, LASSBio-1422 is effective in rodent models of positive and cognitive symptoms of schizophrenia and its ability to bind to D4 and 5-HT1A receptors may at least in part explain its effects in these animal models.
authors.affiliation: aDepartment of Raw Material Production, Post Graduate Program in Pharmaceutical Sciences, Federal University of Rio Grande do Sul, Porto Alegre bBiochemistry and Molecular Pharmacology Laboratory, Institute of Biomedical Sciences cPost Graduate Program in Pharmacology and Medicinal Cheminstry dLaboratory of Evaluation and Synthesis of Bioactive substances, Department of Pharmaceuticals ePost Graduate Program in Chemistry, Institute of Chemistry fDrug Development Research Program, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Andresa H
authors.initials: AH
authors.lastname: Betti
authors.forename: Camila B
authors.initials: CB
authors.lastname: Antonio
authors.forename: Thais E T
authors.initials: TE
authors.lastname: Pompeu
authors.forename: Thaise S
authors.initials: TS
authors.lastname: Martins
authors.forename: Vivian
authors.initials: V
authors.lastname: Herzfeldt
authors.forename: Eveline D
authors.initials: ED
authors.lastname: Stolz
authors.forename: Carlos A M
authors.initials: CA
authors.lastname: Fraga
authors.forename: Eliezer
authors.initials: E
authors.lastname: Barreiro
authors.forename: François
authors.initials: F
authors.lastname: Noël
authors.forename: Stela M K
authors.initials: SM
authors.lastname: Rates
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D050638:Receptors, Dopamine D4 / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D014150:Antipsychotic Agents; C000625838:LASSBio-1422; D010879:Piperazines; D011720:Pyrazoles; D044282:Receptor, Serotonin, 5-HT1A; D050638:Receptors, Dopamine D4