title: Design, synthesis, and evaluation of metabolism-based analogues of haloperidol incapable of forming MPP+-like species.
abstract: The long-term, irreversible, Parkinsonism-like side effects of haloperidol have been speculated to involve several mechanisms. More recently, it has been speculated that the metabolic transformation to MPP+-like species may contribute to the Parkinsonism-like side effects. Because BCPP+ and its reduced analogue have been shown to possess the potential to destroy dopamine receptors in the nigrostriatum, we have designed new analogues of haloperidol lacking the structural features necessary to form neurotoxic quaternary species but retaining their dopamine-binding capacity. The most potent agent at the D2 receptor, the homopiperidine analogue 11, was found to be equipotent to haloperidol. It was also of interest to identify analogues with DA binding profiles similar to that of clozapine at the dopamine receptor subtypes. Evaluation of the proposed agents shows that the ratio of D2 to D4 (2) binding of clozapine was mimicked by 7 [K(i)(D2) = 33, K(i)(D3) = 200, K(i)(D4) = 11 nM; K(i)(D2)/K(i)(D4) = 3] and 9 [K(i)(D2) = 44, K(i)(D3) = 170, K(i)(D4) = 24 nM; K(i)(D2)/K(i)(D4) = 2]. A preliminary in-vivo testing of compound 7 shows that its behavioral profile is similar to that of clozapine. This profile suggests that there is a need for further evaluation of these two synthetic agents and their enantiomers for efficacy and lack of catalepsy in animal models.
authors.affiliation: Division of Basic Pharmaceutical Sciences, Florida A and M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, Florida 32307, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lyles-Eggleston
authors.forename: R
authors.initials: R
authors.lastname: Altundas
authors.forename: J
authors.initials: J
authors.lastname: Xia
authors.forename: D M N
authors.initials: DM
authors.lastname: Sikazwe
authors.forename: P
authors.initials: P
authors.lastname: Fan
authors.forename: Q
authors.initials: Q
authors.lastname: Yang
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.forename: X
authors.initials: X
authors.lastname: Zhu
authors.forename: A W
authors.initials: AW
authors.lastname: Schmidt
authors.forename: M
authors.initials: M
authors.lastname: Vanase-Frawley
authors.forename: A
authors.initials: A
authors.lastname: Shrihkande
authors.forename: A
authors.initials: A
authors.lastname: Villalobos
authors.forename: R F
authors.initials: RF
authors.lastname: Borne
authors.forename: S Y
authors.initials: SY
authors.lastname: Ablordeppey
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002375:Catalepsy / Q000139:chemically induced; D003024:Clozapine / Q000494:pharmacology; D015195:Drug Design; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D010880:Piperidines / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050638:Receptors, Dopamine D4; D013237:Stereoisomerism; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: C482792:4-(4-(4-chlorophenyl)-4-hydroxyazepan-1-yl)-1-(4-fluorophenyl)butan-1-one; D001381:Azepines; C493599:DRD4 protein, human; C493600:Drd4 protein, mouse; C493601:Drd4 protein, rat; D010880:Piperidines; D000644:Quaternary Ammonium Compounds; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D003024:Clozapine; D006220:Haloperidol