title: Targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors for developing effective antipsychotics: synthesis, biological characterization, and behavioral studies.
abstract: Combination of dopamine D3 antagonism, serotonin 5-HT1A partial agonism, and antagonism at 5-HT2A leads to a novel approach to potent atypical antipsychotics. Exploitation of the original structure-activity relationships resulted in the identification of safe and effective antipsychotics devoid of extrapyramidal symptoms liability, sedation, and catalepsy. The potential atypical antipsychotic 5bb was selected for further pharmacological investigation. The distribution of c-fos positive cells in the ventral striatum confirmed the atypical antipsychotic profile of 5bb in agreement with behavioral rodent studies. 5bb administered orally demonstrated a biphasic effect on the MK801-induced hyperactivity at dose levels not able to induce sedation, catalepsy, or learning impairment in passive avoidance. In microdialysis studies, 5bb increased the dopamine efflux in the medial prefrontal cortex. Thus, 5bb represents a valuable lead for the development of atypical antipsychotics endowed with a unique pharmacological profile for addressing negative symptoms and cognitive deficits in schizophrenia.
authors.affiliation: European Research Centre for Drug Discovery and Development, and ‡Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Silvia
authors.initials: S
authors.lastname: Franceschini
authors.forename: Simone
authors.initials: S
authors.lastname: Brogi
authors.forename: Francesco
authors.initials: F
authors.lastname: Trotta
authors.forename: Sindu
authors.initials: S
authors.lastname: Ros
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cagnotto
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.forename: Alice
authors.initials: A
authors.lastname: Casagni
authors.forename: Marco
authors.initials: M
authors.lastname: Andreassi
authors.forename: Simona
authors.initials: S
authors.lastname: Saponara
authors.forename: Beatrice
authors.initials: B
authors.lastname: Gorelli
authors.forename: Pia
authors.initials: P
authors.lastname: Weikop
authors.forename: Jens D
authors.initials: JD
authors.lastname: Mikkelsen
authors.forename: Jorgen
authors.initials: J
authors.lastname: Scheel-Kruger
authors.forename: Karin
authors.initials: K
authors.lastname: Sandager-Nielsen
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry*; D001522:Behavior, Animal; D016291:Dizocilpine Maleate / Q000737:chemistry; D018492:Dopamine Antagonists / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D005260:Female; D007700:Kinetics; D008024:Ligands; D008297:Male; D051379:Mice; D017397:Prefrontal Cortex / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry*; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry*; D050637:Receptors, Dopamine D3 / Q000737:chemistry*; D012559:Schizophrenia / Q000188:drug therapy*; D017366:Serotonin Receptor Agonists / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D050637:Receptors, Dopamine D3; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D016291:Dizocilpine Maleate