title: Pyrrolo[1,3]benzothiazepine-based atypical antipsychotic agents. Synthesis, structure-activity relationship, molecular modeling, and biological studies.
abstract: The prototypical dopamine and serotonin antagonist (+/-)-7-chloro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine (5) was resolved into its R and S enantiomers via crystallization of the diastereomeric tartaric acid salts. Binding studies confirmed that the (R)-(-)-enantiomer is a more potent D(2) receptor antagonist than the (S)-(+)-enantiomer, with almost identical affinity at the 5-HT(2) receptor ((S)-(+)-5, log Y = 4.7; (R)-(-)-5, log Y = 7.4). These data demonstrated a significant stereoselective interaction of 5 at D(2) receptors. Furthermore, enantiomer (S)-(+)-5 (ST1460) was tested on a panel of receptors; this compound showed an intriguing binding profile characterized by high affinity for H(1) and the alpha(1) receptor, a moderate affinity for alpha(2) and D(3) receptors, and low affinity for muscarinic receptors. Pharmacological and biochemical investigation confirmed an atypical pharmacological profile for (S)-(+)-5. This atypical antipsychotic lead has low propensity to induce catalepsy in rat. It has minimal effect on serum prolactin levels, and it has been selected for further pharmacological studies. (S)-(+)-5 increases the extracellular levels of dopamine in the rat striatum after subcutaneous administration. By use of 5 as the lead compound, a novel series of potential atypical antipsychotics has been developed, some of them being characterized by a stereoselective interaction at D(2) receptors. A number of structure-activity relationships trends have been identified, and a possible explanation is advanced in order to account for the observed stereoselectivity of the enantiomer of (+/-)-5 for D(2) receptors. The molecular structure determination of the enantiomers of 5 by X-ray diffraction and molecular modeling is reported.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Universitá degli Studi di Siena, Via Aldo Moro, 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: Sandra
authors.initials: S
authors.lastname: Gemma
authors.forename: Vito
authors.initials: V
authors.lastname: Nacci
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
authors.forename: Bruno
authors.initials: B
authors.lastname: Catalanotti
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giorgi
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cagnotto
authors.forename: Mara
authors.initials: M
authors.lastname: Goegan
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: Domenico
authors.initials: D
authors.lastname: Mastroianni
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Scafetta
authors.forename: Bruno
authors.initials: B
authors.lastname: Galletti
authors.forename: M Antonietta
authors.initials: MA
authors.lastname: Stasi
authors.forename: Massimo
authors.initials: M
authors.lastname: Castorina
authors.forename: Licia
authors.initials: L
authors.lastname: Pacifici
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: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D018360:Crystallography, X-Ray; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D017551:Microdialysis; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011388:Prolactin / Q000097:blood; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis* / Q000737:chemistry / 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; D011758:Pyrroles; D017448:Receptors, Dopamine D2; D013841:Thiazepines; D015102:3,4-Dihydroxyphenylacetic Acid; D011388:Prolactin; D004298:Dopamine; D006719:Homovanillic Acid