title: The acute EPS of haloperidol may be unrelated to its metabolic transformation to BCPP+.
abstract: We have previously proposed that haloperidol's debilitating extrapyramidal symptoms (EPS) may be associated with its quaternary BCPP+ (an MPP+ like species) metabolite formed in vivo. However, recent work on D2 knock out mice suggests that haloperidol's EPS may be related to its potent D2 binding (K(i)=0.9 nM). In this study, we explore this question by synthesizing and testing an analogue (DS-27) that binds to D2 receptors with higher affinity than haloperidol, but cannot form quaternary metabolites. This study suggests that D2 affinity may be the primary underlying mechanism for acute catalepsy induction by haloperidol.
authors.affiliation: College of Pharmacy & Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL 32307, USA.
authors.forename: Donald M N
authors.initials: DM
authors.lastname: Sikazwe
authors.forename: Shouming
authors.initials: S
authors.lastname: Li
authors.forename: Margaret
authors.initials: M
authors.lastname: Lyles-Eggleston
authors.forename: Seth Y
authors.initials: SY
authors.lastname: Ablordeppey
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001058:Apomorphine / Q000494:pharmacology; D001480:Basal Ganglia Diseases / Q000139:chemically induced*; D002352:Carrier Proteins / Q000378:metabolism* / Q000633:toxicity*; D002375:Catalepsy / Q000139:chemically induced; D018491:Dopamine Agonists / Q000494:pharmacology; D054889:Fatty Acid Synthase, Type II; D006220:Haloperidol / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D051379:Mice; D011597:Psychomotor Performance / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D002352:Carrier Proteins; D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; D054889:Fatty Acid Synthase, Type II; D000103:Acetyl-CoA Carboxylase; C079633:biotin carboxyl carrier protein; D006220:Haloperidol; D001058:Apomorphine