Pyrrolo[1,3]benzothiazepine-based atypical antipsychotic agents. Synthesis, structure-activity relationship, molecular modeling, and biological studies.
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.
Campiani
Giuseppe
G
Dipartimento Farmaco Chimico Tecnologico, Universitá degli Studi di Siena, Via Aldo Moro, 53100 Siena, Italy. campiani@unisi.it
Butini
Stefania
S
Gemma
Sandra
S
Nacci
Vito
V
Fattorusso
Caterina
C
Catalanotti
Bruno
B
Giorgi
Gianluca
G
Cagnotto
Alfredo
A
Goegan
Mara
M
Mennini
Tiziana
T
Minetti
Patrizia
P
Di Cesare
M Assunta
MA
Mastroianni
Domenico
D
Scafetta
Nazzareno
N
Galletti
Bruno
B
Stasi
M Antonietta
MA
Castorina
Massimo
M
Pacifici
Licia
L
Ghirardi
Orlando
O
Tinti
Ornella
O
Carminati
Paolo
P
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
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