HPP+ explained
| Drug Name: | HPP+ |
| Width: | 250px |
| Class: | Monoaminergic neurotoxin |
| Atc Prefix: | None |
| Cas Number: | 125785-69-5 |
| Pubchem: | 9975463 |
| Drugbank: | DBMET01212 |
| Chemspiderid: | 8151055 |
| Unii: | 47Z7A2W953 |
| Chebi: | 178132 |
| Chembl: | 1269 |
| Synonyms: | Haloperidol pyridinium; Haloperidol pyridinium ion; Haloperidol pyridinium cation; BCPP+; 4-CFOBP; 4-(4-Chlorophenyl)-1-(4-(4-fluorophenyl)-4-oxobutyl)pyridinium |
| Iupac Name: | 4-[4-(4-chlorophenyl)pyridin-1-ium-1-yl]-1-(4-fluorophenyl)butan-1-one |
| C: | 21 |
| H: | 18 |
| Cl: | 1 |
| F: | 1 |
| N: | 1 |
| O: | 1 |
| Charge: | + |
| Smiles: | C1=CC(=CC=C1C2=CC=[N+](C=C2)CCCC(=O)C3=CC=C(C=C3)F)Cl |
| Stdinchi: | 1S/C21H18ClFNO/c22-19-7-3-16(4-8-19)17-11-14-24(15-12-17)13-1-2-21(25)18-5-9-20(23)10-6-18/h3-12,14-15H,1-2,13H2/q+1 |
| Stdinchikey: | KAPIKUHBALFONG-UHFFFAOYSA-N |
HPP+, also known as haloperidol pyridinium, is a monoaminergic neurotoxin and a metabolite of haloperidol.[1] [2] [3]
Formation and metabolism
HPP+ is formed from haloperidol, and its dehydration product HPTP, by CYP3A enzymes in the liver.[4] The compound can cross the blood–brain barrier and has been detected in the brain following haloperidol administration in both animals and humans.
Neurotoxicity
HPP+ is structurally related to the selective dopaminergic neurotoxin MPTP (and its active metabolite MPP+), which induces Parkinson's disease-like symptoms in humans. HPP+ is a neurotoxin specifically affecting serotonergic and dopaminergic neurons, and its neurotoxicity resembles that of MPTP.
Extrapyramidal symptoms (EPS)
HPP+ may contribute to the development of extrapyramidal symptoms (EPS) in patients undergoing long-term haloperidol therapy. An alternative theory posits that these symptoms result from long-term dopamine receptor supersensitivity, rather than direct neurotoxicity.
Discovery
HPP+ was first identified as a neurotoxic metabolite of haloperidol in 1990 and 1991, many years after haloperidol was introduced clinically and following the discovery of MPTP.[5] [6] [7]
Additional metabolites
Besides HPP+, another reactive metabolite of haloperidol, RHPP+, has been detected in humans. The parent form of RHPP+ is RHPTP.[8]
Notes and References
- Book: Kostrzewa RM . Handbook of Neurotoxicity . Survey of Selective Monoaminergic Neurotoxins Targeting Dopaminergic, Noradrenergic, and Serotoninergic Neurons . Springer International Publishing . Cham . 2022 . 978-3-031-15079-1 . 10.1007/978-3-031-15080-7_53 . 159–198.
- Igarashi . Kazuo . The Possible Role of an Active Metabolite Derived from the Neuroleptic Agent Haloperidol in Drug-Induced Parkinsonism . Journal of Toxicology: Toxin Reviews . 17 . 1 . 1998 . 0731-3837 . 10.3109/15569549809006488 . 27–38.
- Górska A, Marszałł M, Sloderbach A . [The neurotoxicity of pyridinium metabolites of haloperidol] . Polish . Postepy Higieny I Medycyny Doswiadczalnej . 69 . 1169–1175 . October 2015 . 26561842 . 10.5604/17322693.1175009 . 1 November 2024 . The neurotoxicity of pyridinium metabolites of haloperidol . free .
- Castagnoli N, Castagnoli KP, Van der Schyf CJ, Usuki E, Igarashi K, Steyn SJ, Riker RR . Enzyme-catalyzed bioactivation of cyclic tertiary amines to form potential neurotoxins . Polish Journal of Pharmacology . 51 . 1 . 31–38 . 1999 . 10389142 .
- Subramanyam B, Rollema H, Woolf T, Castagnoli N . Identification of a potentially neurotoxic pyridinium metabolite of haloperidol in rats . Biochemical and Biophysical Research Communications . 166 . 1 . 238–244 . January 1990 . 2302206 . 10.1016/0006-291x(90)91936-m .
- Subramanyam B, Woolf T, Castagnoli N . Studies on the in vitro conversion of haloperidol to a potentially neurotoxic pyridinium metabolite . Chemical Research in Toxicology . 4 . 1 . 123–128 . 1991 . 1912294 . 10.1021/tx00019a017 .
- Subramanyam B, Pond SM, Eyles DW, Whiteford HA, Fouda HG, Castagnoli N . Identification of potentially neurotoxic pyridinium metabolite in the urine of schizophrenic patients treated with haloperidol . Biochemical and Biophysical Research Communications . 181 . 2 . 573–578 . December 1991 . 1755839 . 10.1016/0006-291x(91)91228-5 .
- Avent KM, DeVoss JJ, Gillam EM . Cytochrome P450-mediated metabolism of haloperidol and reduced haloperidol to pyridinium metabolites . Chem Res Toxicol . 19 . 7 . 914–920 . July 2006 . 16841959 . 10.1021/tx0600090 .
