title: New antipsychotic agents with serotonin and dopamine antagonist properties based on a pyrrolo[2,1-b][1,3]benzothiazepine structure.
abstract: The development of a synthetic approach to the novel pyrrolo[2, 1-b][1,3]benzothiazepine and its derivatives and their biological evaluation as potential antipsychotic drugs are described. In binding studies these compounds proved to be potent 5-HT2, D2, and D3 receptor ligands. The more potent benzothiazepine (+/-)-3b was resolved into its enantiomers by using HPLC techniques. In vitro testing confirmed that (-)-3b is a more potent D2 receptor ligand, maintaining high affinity for 5-HT2 receptors. In contrast, the (+)-3b enantiomer presents a 35 times higher affinity for 5-HT2 than for dopamine D2 receptors with a similar dopamine D1 receptor affinity to that of (-)-3b. Overall, (+)-3b shows an "atypical" neuroleptic binding profile, while (-)-3b has a more "classical" profile. Furthermore pharmacological and biochemical testing displayed that the novel benzothiazepine (+/-)-3b is able to increase the extracellular levels of dopamine in the rat striatum and causes a dose-related suppression of apomorphine-induced locomotor activity. At low doses (+/-)-3b does not induce catalepsy, showing atypical antipsychotic properties similar to those of olanzapine. These heterocyclic compouds represent new leads for the development of novel antipsychotic drugs with atypical properties.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Universita' di Siena, Banchi di Sotto, 55, 53100 Siena, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Campiani
authors.forename: V
authors.initials: V
authors.lastname: Nacci
authors.forename: S
authors.initials: S
authors.lastname: Bechelli
authors.forename: S M
authors.initials: SM
authors.lastname: Ciani
authors.forename: A
authors.initials: A
authors.lastname: Garofalo
authors.forename: I
authors.initials: I
authors.lastname: Fiorini
authors.forename: H
authors.initials: H
authors.lastname: Wikström
authors.forename: P
authors.initials: P
authors.lastname: de Boer
authors.forename: Y
authors.initials: Y
authors.lastname: Liao
authors.forename: P G
authors.initials: PG
authors.lastname: Tepper
authors.forename: A
authors.initials: A
authors.lastname: Cagnotto
authors.forename: T
authors.initials: T
authors.lastname: Mennini
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: C114807:7-chloro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo(2,1-b)(1,3)benzothiazepine; D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; D011758:Pyrroles; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013841:Thiazepines; D015102:3,4-Dihydroxyphenylacetic Acid; D004298:Dopamine