HPP⁺

HPP⁺
Clinical data
Other names	Haloperidol pyridinium; Haloperidol pyridinium ion; Haloperidol pyridinium cation; BCPP+; 4-CFOBP; 4-(4-Chlorophenyl)-1-(4-(4-fluorophenyl)-4-oxobutyl)pyridinium
Drug class	Monoaminergic neurotoxin
ATC code	None;
Identifiers
	IUPAC name 4-[4-(4-chlorophenyl)pyridin-1-ium-1-yl]-1-(4-fluorophenyl)butan-1-one;
CAS Number	125785-69-5;
PubChem CID	9975463;
DrugBank	DBMET01212;
ChemSpider	8151055;
UNII	47Z7A2W953;
ChEBI	CHEBI:178132;
ChEMBL	ChEMBL1269;
CompTox Dashboard (EPA)	DTXSID00154895 ;
Chemical and physical data
Formula	C21H18ClFNO+
Molar mass	354.83 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1=CC(=CC=C1C2=CC=[N+](C=C2)CCCC(=O)C3=CC=C(C=C3)F)Cl;
	InChI InChI=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; Key: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.^[1]^[2]^[4] The compound can cross the blood–brain barrier and has been detected in the brain following haloperidol administration in both animals and humans.^[2]

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.^[1]^[2] HPP⁺ is a neurotoxin specifically affecting serotonergic and dopaminergic neurons, and its neurotoxicity resembles that of MPTP.^[2]

Extrapyramidal symptoms (EPS)

HPP⁺ may contribute to the development of extrapyramidal symptoms (EPS) in patients undergoing long-term haloperidol therapy.^[2] An alternative theory posits that these symptoms result from long-term dopamine receptor supersensitivity, rather than direct neurotoxicity.^[2]

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.^[2]^[5]^[6]^[7]

Additional metabolites

Besides HPP⁺, another reactive metabolite of haloperidol, RHPP⁺, has been detected in humans.^[1]^[2] The parent form of RHPP⁺ is RHPTP.^[8]

References

^ ^a ^b ^c ^d Kostrzewa RM (2022). "Survey of Selective Monoaminergic Neurotoxins Targeting Dopaminergic, Noradrenergic, and Serotoninergic Neurons". Handbook of Neurotoxicity. Cham: Springer International Publishing. pp. 159–198. doi:10.1007/978-3-031-15080-7_53. ISBN 978-3-031-15079-1.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Igarashi K (1998). "The Possible Role of an Active Metabolite Derived from the Neuroleptic Agent Haloperidol in Drug-Induced Parkinsonism". Journal of Toxicology: Toxin Reviews. 17 (1): 27–38. doi:10.3109/15569549809006488. ISSN 0731-3837.
^ Górska A, Marszałł M, Sloderbach A (October 2015). "[The neurotoxicity of pyridinium metabolites of haloperidol]" [The neurotoxicity of pyridinium metabolites of haloperidol]. Postepy Higieny I Medycyny Doswiadczalnej (in Polish). 69: 1169–1175. doi:10.5604/17322693.1175009 (inactive 1 November 2024). PMID 26561842.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
^ Castagnoli N, Castagnoli KP, Van der Schyf CJ, Usuki E, Igarashi K, Steyn SJ, et al. (1999). "Enzyme-catalyzed bioactivation of cyclic tertiary amines to form potential neurotoxins". Polish Journal of Pharmacology. 51 (1): 31–38. PMID 10389142.
^ Subramanyam B, Rollema H, Woolf T, Castagnoli N (January 1990). "Identification of a potentially neurotoxic pyridinium metabolite of haloperidol in rats". Biochemical and Biophysical Research Communications. 166 (1): 238–244. doi:10.1016/0006-291x(90)91936-m. PMID 2302206.
^ Subramanyam B, Woolf T, Castagnoli N (1991). "Studies on the in vitro conversion of haloperidol to a potentially neurotoxic pyridinium metabolite". Chemical Research in Toxicology. 4 (1): 123–128. doi:10.1021/tx00019a017. PMID 1912294.
^ Subramanyam B, Pond SM, Eyles DW, Whiteford HA, Fouda HG, Castagnoli N (December 1991). "Identification of potentially neurotoxic pyridinium metabolite in the urine of schizophrenic patients treated with haloperidol". Biochemical and Biophysical Research Communications. 181 (2): 573–578. doi:10.1016/0006-291x(91)91228-5. PMID 1755839.
^ Avent KM, DeVoss JJ, Gillam EM (July 2006). "Cytochrome P450-mediated metabolism of haloperidol and reduced haloperidol to pyridinium metabolites". Chem Res Toxicol. 19 (7): 914–920. doi:10.1021/tx0600090. PMID 16841959.

[Kostrzewa2022-1] Kostrzewa RM (2022). "Survey of Selective Monoaminergic Neurotoxins Targeting Dopaminergic, Noradrenergic, and Serotoninergic Neurons". Handbook of Neurotoxicity. Cham: Springer International Publishing. pp. 159–198. doi:10.1007/978-3-031-15080-7_53. ISBN 978-3-031-15079-1.

[Igarashi1998-2] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Igarashi K (1998). "The Possible Role of an Active Metabolite Derived from the Neuroleptic Agent Haloperidol in Drug-Induced Parkinsonism". Journal of Toxicology: Toxin Reviews. 17 (1): 27–38. doi:10.3109/15569549809006488. ISSN 0731-3837.

[GórskaMarszałłSloderbach2015-3] Górska A, Marszałł M, Sloderbach A (October 2015). "[The neurotoxicity of pyridinium metabolites of haloperidol]" [The neurotoxicity of pyridinium metabolites of haloperidol]. Postepy Higieny I Medycyny Doswiadczalnej (in Polish). 69: 1169–1175. doi:10.5604/17322693.1175009 (inactive 1 November 2024). PMID 26561842.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)

[CastagnoliCastagnoliVanderSchyf1999-4] Castagnoli N, Castagnoli KP, Van der Schyf CJ, Usuki E, Igarashi K, Steyn SJ, et al. (1999). "Enzyme-catalyzed bioactivation of cyclic tertiary amines to form potential neurotoxins". Polish Journal of Pharmacology. 51 (1): 31–38. PMID 10389142.

[SubramanyamRollemaWoolf1990-5] Subramanyam B, Rollema H, Woolf T, Castagnoli N (January 1990). "Identification of a potentially neurotoxic pyridinium metabolite of haloperidol in rats". Biochemical and Biophysical Research Communications. 166 (1): 238–244. doi:10.1016/0006-291x(90)91936-m. PMID 2302206.

[SubramanyamWoolfCastagnoli1991-6] Subramanyam B, Woolf T, Castagnoli N (1991). "Studies on the in vitro conversion of haloperidol to a potentially neurotoxic pyridinium metabolite". Chemical Research in Toxicology. 4 (1): 123–128. doi:10.1021/tx00019a017. PMID 1912294.

[SubramanyamPondEyles1991-7] Subramanyam B, Pond SM, Eyles DW, Whiteford HA, Fouda HG, Castagnoli N (December 1991). "Identification of potentially neurotoxic pyridinium metabolite in the urine of schizophrenic patients treated with haloperidol". Biochemical and Biophysical Research Communications. 181 (2): 573–578. doi:10.1016/0006-291x(91)91228-5. PMID 1755839.

[AventDeVossGillam2006-8] Avent KM, DeVoss JJ, Gillam EM (July 2006). "Cytochrome P450-mediated metabolism of haloperidol and reduced haloperidol to pyridinium metabolites". Chem Res Toxicol. 19 (7): 914–920. doi:10.1021/tx0600090. PMID 16841959.

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HPP+