title: Novel atypical antipsychotic agents: rational design, an efficient palladium-catalyzed route, and pharmacological studies.
abstract: Using rational drug design to develop atypical antipsychotic drug candidates, we generated novel and metabolically stable pyrrolobenzazepines with an optimized pK(i) 5-HT(2A)/D(2) ratio. 5a, obtained by a new palladium-catalyzed three-step synthesis, was selected for further pharmacological and biochemical investigations and showed atypical antipsychotic properties in vivo. 5a was active on conditioned avoidance response at 0.56 mg/kg, it had low cataleptic potential and proved to be better than ST1899, clozapine, and olanzapine, representing a new clinical candidate.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Via Aldo Moro, and European Research Centre for Drug Discovery and Development, Università di Siena, 53100 Siena, Italy. campiani@unisi.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
authors.forename: Francesco
authors.initials: F
authors.lastname: Trotta
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.forename: Bruno
authors.initials: B
authors.lastname: Catalanotti
authors.forename: Vito
authors.initials: V
authors.lastname: Nacci
authors.forename: Isabella
authors.initials: I
authors.lastname: Fiorini
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cagnotto
authors.forename: Ilario
authors.initials: I
authors.lastname: Mereghetti
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mennini
authors.forename: Patrizia
authors.initials: P
authors.lastname: Minetti
authors.forename: M Assunta
authors.initials: MA
authors.lastname: Di Cesare
authors.forename: M Antonietta
authors.initials: MA
authors.lastname: Stasi
authors.forename: Stefano
authors.initials: S
authors.lastname: Di Serio
authors.forename: Orlando
authors.initials: O
authors.lastname: Ghirardi
authors.forename: Ornella
authors.initials: O
authors.lastname: Tinti
authors.forename: Paolo
authors.initials: P
authors.lastname: Carminati
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002375:Catalepsy / Q000139:chemically induced; D002384:Catalysis; D002460:Cell Line; D018360:Crystallography, X-Ray; D065127:Dopamine D2 Receptor Antagonists; D015195:Drug Design; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010165:Palladium; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry; D017448:Receptors, Dopamine D2 / Q000737:chemistry; D058830:Serotonin 5-HT2 Receptor Antagonists; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D001552:Benzazepines; D065127:Dopamine D2 Receptor Antagonists; D011758:Pyrroles; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D058830:Serotonin 5-HT2 Receptor Antagonists; D010165:Palladium