title: Benzo- and thienobenzo- diazepines: multi-target drugs for CNS disorders.
abstract: Benzodiazepines (BZ or BZD) are a class of gabaminergic psychoactive chemicals used in hypnotics, sedation, in the treatment of anxiety, and in other CNS disorders. These drugs include alprazolam (Xanax), diazepam (Valium), clonazepam (Klonopin), and others. There are two distinct types of pharmacological binding sites for benzodiazepines in the brain (BZ1 and BZ2), these sites are on GABA-A receptors, and are classified as short, intermediate, or long-acting. From the thienobenzodiazepine class (TBZ), Olanzapine (2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine) (Zyprexa) was used as an example to demonstrate the antagonism of this class of compounds for multiples receptors including: dopamine D1-D5, α-adrenoreceptor, histamine H1, muscarinic M1-M5 and 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3 and 5-HT6 receptors. Olanzapine is an atypical antipsychotic agent, structurally related to clozapine, and extensively used for the treatment of schizophrenia, bipolar disorder-associated mania, and the behavioral symptoms of Alzheimer's disease. The functional blockade of these multiple receptors contributes to the wide range of its pharmacologic and therapeutic activities, having relatively few side effects when compared to other antipsychotics agents. Thienobenzodiazepines (such as Olanzapine) are characterized as multi- receptor- targeted- acting- agents. This mini-review discusses these 2 drug classes that act on the central nervous system, the main active compounds used, and the various receptors with which they interact. In addition, we propose 12 olanzapine analogues, and generated Random Forest models, from a data set obtained from the ChEMBL database, to classify the structures as active or inactive against 5 dopamine receptors (D1, D2, D3, D4, D5 and D6), and dopamine transporter.
authors.forename: F J B
authors.initials: FJ
authors.lastname: Mendonça Júnior
authors.affiliation: Health Sciences Center, Federal University of Paraiba, Campus I, 58051-970, Joao Pessoa, PB, Brazil. luciana.scotti@gmail.com.
authors.forename: L
authors.initials: L
authors.lastname: Scotti
authors.forename: H
authors.initials: H
authors.lastname: Ishiki
authors.forename: S P S
authors.initials: SP
authors.lastname: Botelho
authors.forename: M S
authors.initials: MS
authors.lastname: Da Silva
authors.forename: M T
authors.initials: MT
authors.lastname: Scotti
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001569:Benzodiazepines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002493:Central Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D000077152:Olanzapine; D064798:Polypharmacology; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D000077152:Olanzapine; D011942:Receptors, Adrenergic, alpha; D011954:Receptors, Dopamine; D011969:Receptors, Histamine H1; D011976:Receptors, Muscarinic; D017367:Selective Serotonin Reuptake Inhibitors; D005680:gamma-Aminobutyric Acid