title: Partial agonism and fast dissociation of LASSBio-579 at dopamine D2 receptor.
abstract: In an attempt to better understand the molecular mechanism of action of the antipsychotic lead LASSBio-579 and of its main metabolite LQFM 037, the aim of this work was to evaluate their intrinsic activity and binding kinetics at the dopamine D2 receptor. In transfected HEK cells expressing the D2L receptor under an inducible promoter, LASSBio-579 and LQFM 037, but not clozapine, behaved as weak partial agonists in [(35)S]-GTPγS binding assays performed in optimized conditions previously shown to evidence the partial agonist profile of aripiprazole. Besides, data obtained in radioligand competition assays on rat striatal membranes suggested a rapid association to and dissociation from the D2-like receptors. Using the kinetic rate index based on the strategy of the dual-point competition association assay, we showed that our compounds share a similar kinetic profile with clozapine, distinct from the typical antipsychotic haloperidol. These two characteristics could contribute to the atypical-like profile observed after administration of LASSBio-579 to rodents, in models of positive and negative symptoms of schizophrenia.
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; Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, 373, Sala K2-27, CEP 21941-912 Ilha do Fundão, Rio de Janeiro, Brazil.
authors.forename: Thais Emanoelle T
authors.initials: TE
authors.lastname: Pompeu
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; Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, 373, Sala K2-27, CEP 21941-912 Ilha do Fundão, Rio de Janeiro, Brazil.
authors.forename: Fernando
authors.initials: F
authors.lastname: Monteiro do Monte
authors.affiliation: Institute of Neuroscience (IoNS), Group of Neuropharmacology, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bosier
authors.affiliation: Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, 373, Sala K2-27, CEP 21941-912 Ilha do Fundão, Rio de Janeiro, Brazil; Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, 373, Bloco Bss 022, CEP 21944-971 Ilha do Fundão, Rio de Janeiro, Brazil.
authors.forename: Carlos A M
authors.initials: CA
authors.lastname: Fraga
authors.affiliation: Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, 373, Sala K2-27, CEP 21941-912 Ilha do Fundão, Rio de Janeiro, Brazil; Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, 373, Bloco Bss 022, CEP 21944-971 Ilha do Fundão, Rio de Janeiro, Brazil.
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.affiliation: Laboratório de Bioconversão, LabMol and Laboratório de Química Farmacêutica, Medicinal, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Menegatti
authors.affiliation: Institute of Neuroscience (IoNS), Group of Neuropharmacology, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Hermans
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; Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, 373, Sala K2-27, CEP 21941-912 Ilha do Fundão, Rio de Janeiro, Brazil. Electronic address: fnoel@pharma.ufrj.br.
authors.forename: François
authors.initials: F
authors.lastname: Noël
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D057809:HEK293 Cells; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D010879:Piperazines / Q000494:pharmacology*; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; C518328:LASSBio-579; D010879:Piperazines; D017448:Receptors, Dopamine D2; C113776:dopamine D2L receptor; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000068180:Aripiprazole; D003024:Clozapine; D006220:Haloperidol
keywords: Atypical antipsychotics; Clozapine; Dissociation kinetics; Intrinsic activity; Residence time; Schizophrenia