title: QF2004B, a potential antipsychotic butyrophenone derivative with similar pharmacological properties to clozapine.
abstract: The aim of the present work was to characterize a lead compound displaying relevant multi-target interactions, and with an in vivo behavioral profile predictive of atypical antipsychotic activity. Synthesis, molecular modeling and in vitro and in vivo pharmacological studies were carried out for 2-[4-(6-fluorobenzisoxazol-3-yl)piperidinyl]methyl-1,2,3,4-tetrahydro-carbazol-4-one (QF2004B), a conformationally constrained butyrophenone analogue. This compound showed a multi-receptor profile with affinities similar to those of clozapine for serotonin (5-HT2A, 5-HT1A, and 5-HT2C), dopamine (D1, D2, D3 and D4), alpha-adrenergic (alpha1, alpha2), muscarinic (M1, M2) and histamine H1 receptors. In addition, QF2004B mirrored the antipsychotic activity and atypical profile of clozapine in a broad battery of in vivo tests including locomotor activity (ED50 = 1.19 mg/kg), apomorphine-induced stereotypies (ED50 = 0.75 mg/kg), catalepsy (ED50 = 2.13 mg/kg), apomorphine- and DOI (2,5-dimethoxy-4-iodoamphetamine)-induced prepulse inhibition (PPI) tests. These results point to QF2004B as a new lead compound with a relevant multi-receptor interaction profile for the discovery and development of new antipsychotics.
authors.affiliation: Departamento de Farmacología, Universidad de Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Brea
authors.forename: Marián
authors.initials: M
authors.lastname: Castro
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Loza
authors.forename: Christian F
authors.initials: CF
authors.lastname: Masaguer
authors.forename: Enrique
authors.initials: E
authors.lastname: Raviña
authors.forename: Cristina
authors.initials: C
authors.lastname: Dezi
authors.forename: Manuel
authors.initials: M
authors.lastname: Pastor
authors.forename: Ferran
authors.initials: F
authors.lastname: Sanz
authors.forename: Araceli
authors.initials: A
authors.lastname: Cabrero-Castel
authors.forename: Beatriz
authors.initials: B
authors.lastname: Galán-Rodríguez
authors.forename: Emilio
authors.initials: E
authors.lastname: Fernández-Espejo
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.forename: Patricia
authors.initials: P
authors.lastname: Robledo
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002090:Butyrophenones / Q000494:pharmacology*; D016466:CHO Cells; D002227:Carbazoles / Q000494:pharmacology*; D002375:Catalepsy / Q000188:drug therapy; D003024:Clozapine / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D002090:Butyrophenones; D002227:Carbazoles; D007555:Isoxazoles; C409482:QF 2004B; D011942:Receptors, Adrenergic, alpha; D011954:Receptors, Dopamine; D011969:Receptors, Histamine H1; D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin; D003024:Clozapine