Chemistry:Melperone

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Short description: Antipsychotic drug
Melperone
Skeletal formula of melperone
Space-filling model of the melperone molecule
Clinical data
Trade namesBuronil
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral, intramuscular injection
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability87% (IM), 54% (Oral via syrup), 65% (Oral, tablet)[1]
Protein binding50%
MetabolismHepatic
Elimination half-life3–4 hours (oral)[1]
6 hours (IM)
ExcretionRenal (70% as metabolites, 5.5–10.4% as unchanged drug)[1][2]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC16H22FNO
Molar mass263.356 g·mol−1
3D model (JSmol)
  (verify)

Melperone (Bunil (PT), Buronil (AT, BE, CZ, Denmark , Finland †, NL†, Norway †, SE), Eunerpan (Germany ))[3] is an atypical antipsychotic of the butyrophenone chemical class, making it structurally related to the typical antipsychotic haloperidol. It first entered clinical use in 1960s.[4]

Marketing and indications

It has been tried in treatment-resistant cases of schizophrenia with some (albeit limited) success.[4][5][6][7] It has also been reported effective in the treatment of L-DOPA and other forms of psychosis in Parkinson's disease[8] (although a multicentre, double-blind, placebo-controlled study conducted in 2012 failed to support these findings[9]). It is also known to possess anxiolytic properties.[10] It is marketed in the following countries:[3][11]


Adverse effects

Melperone is reported to produce significantly less weight gain than clozapine and approximately as much weight gain as typical antipsychotics.[12] It is also purported to produce around as much prolactin secretion as clozapine (which is virtually nil).[13] It is also purported to produce sedative effects[14] and QT interval prolongation.[15] It is also known to produce less extrapyramidal side effects than the first-generation (typical) antipsychotic, thiothixene.[16] It can also produce (usually relatively mild) dry mouth.[17]

Other common adverse effects include[2][18][19]
  • Constipation
  • Diarrhea
  • Nausea
  • Vomiting
  • Appetite loss
  • Hypersalivation (drooling)
  • Extrapyramidal side effects (e.g. tremor, dystonia, hypokinesis, akathisia, dyskinesias)
  • Insomnia
  • Agitation
  • Headache
  • Dizziness
  • Fatigue
  • Miosis
  • Mydriasis
  • Blurred vision
  • Elevated liver enzymes (esp. ALT and GGTP)


Rare adverse effects include[2][18][19]
Unknown frequency adverse effects include[2][18][19]
  • Seizures (probably rare/uncommon)
  • Increased intraocular pressure
  • Intrahepatic cholestasis (probably rare)
  • Orthostatic hypotension (probably common)
  • Arrhythmias
  • Rash
  • Hyperprolactinemia (which can lead to e.g. galactorrhea, gynecomastia)
  • Weight gain
  • Increased appetite


Interactions

Melperone is reported to be a CYP2D6 inhibitor.[20][21][22]

Pharmacology

Melperone binds to the dopamine D2 receptor, just like all other clinically-utilized antipsychotics, but it does so with a very low affinity and hence may be liable to rapidly dissociate from the D2 receptor hence potentially giving it the profile of an atypical antipsychotic.[23]

Receptor Ki [nM][24]
5-HT1A 2,200
5-HT1D 3,400
5-HT2A 230
5-HT2C 2,100
5-HT6 1,254
5-HT7 578
α1 180
α2 150
M1 >10,000
M2 2,400
M3 >10,000
M4 4,400
M5 >10,000
D2 194
D3 347
D4 555
H1 580

Synthesis

Thieme Patents:[25][26] 86%:[27]

For the last step of the synthesis the sidechain 4-Chloro-4'-Fluorobutyrophenone [3874-54-2] (1) is attached to 4-Methylpiperidine (4-Pipecoline) [626-58-4] (2).

See also

References

  1. ↑ 1.0 1.1 1.2 "Pharmacokinetics of parenteral and oral melperone in man". European Journal of Clinical Pharmacology 23 (2): 173–6. 1982. doi:10.1007/BF00545974. PMID 7140807. 
  2. ↑ 2.0 2.1 2.2 2.3 Product Information: Eunerpan(R), Melperonhydrochlorid (Report). Knoll Deutschland GmbH, Ludwigshafen. 1995. 
  3. ↑ 3.0 3.1 Melperone Hydrochloride. The Royal Pharmaceutical Society of Great Britain. 30 January 2013. http://www.medicinescomplete.com/mc/martindale/current/11022-r.htm. Retrieved 3 November 2013. 
  4. ↑ 4.0 4.1 "Auditing clinical outcomes after introducing off-licence prescribing of atypical antipsychotic melperone for patients with treatment refractory schizophrenia". TheScientificWorldJournal 2012: 512047. 2012. doi:10.1100/2012/512047. PMID 22566771. 
  5. ↑ "Melperone in treatment-refractory schizophrenia: a case series". Therapeutic Advances in Psychopharmacology 1 (1): 19–23. February 2011. doi:10.1177/2045125311399800. PMID 23983923. 
  6. ↑ "Melperone in the treatment of neuroleptic-resistant schizophrenia". Psychiatry Research 105 (3): 201–9. December 2001. doi:10.1016/s0165-1781(01)00346-8. PMID 11814539. 
  7. ↑ "Melperone, an atypical antipsychotic drug, in the treatment of schizophrenia: dose-response analysis on effectiveness and tolerability, and efficacy for treatment-resistant schizophrenia and cognitive function". International Clinical Psychopharmacology 19 (3): 184. 2004. doi:10.1097/00004850-200405000-00039. 
  8. ↑ Barbato L, Monge A, Stocchi F, Nordera G. Melperone in the treatment of iatrogenic psychosis in Parkinson’s disease. Funct Neurol. 1996 Aug;11(4):201–7.
  9. ↑ "Melperone is ineffective in treating Parkinson's disease psychosis". Movement Disorders 27 (6): 803–4. May 2012. doi:10.1002/mds.24942. PMID 22362330. 
  10. ↑ "Melperone in low doses in anxious neurotic patients. A double-blind placebo-controlled clinical study". Neuropsychobiology 11 (3): 181–6. 1984. doi:10.1159/000118074. PMID 6147789. 
  11. ↑ "Buronil generic. Price of buronil. Uses, Dosage, Side effects". https://www.ndrugs.com/?s=buronil. 
  12. ↑ "Changes in weight and body mass index during treatment with melperone, clozapine and typical neuroleptics". Psychiatry Research 176 (2–3): 114–9. April 2010. doi:10.1016/j.psychres.2009.03.026. PMID 20199813. 
  13. ↑ "Melperone, an aytpical antipsychotic drug with clozapine-like effect on plasma prolactin: contrast with typical neuroleptics". Human Psychopharmacology 24 (5): 415–22. July 2009. doi:10.1002/hup.1036. PMID 19551763. 
  14. ↑ "Sedative effects and prolactin response to single oral doses of melperone". Psychopharmacology 79 (2–3): 142–7. 1983. doi:10.1007/bf00427801. PMID 6133301. 
  15. ↑ "Melperone: electrophysiologic and antiarrhythmic activity in humans". Journal of Cardiovascular Pharmacology 15 (1): 144–9. January 1990. doi:10.1097/00005344-199001000-00023. PMID 1688972. 
  16. ↑ "Melperone in the treatment of schizophrenia". Acta Psychiatrica Scandinavica. Supplementum 352: 35–9. 1989. doi:10.1111/j.1600-0447.1989.tb06434.x. PMID 2479227. 
  17. ↑ "Effect of single oral doses of various neuroleptic drugs on salivary secretion rate, pH, and buffer capacity in healthy subjects". Psychopharmacology 75 (2): 114–8. 1981. doi:10.1007/bf00432171. PMID 6119724. 
  18. ↑ 18.0 18.1 18.2 "Additional studies on side effects of melperone in long-term therapy for 1 to 15 years in psychiatric patients". Arzneimittel-Forschung 31 (4): 737–40. 1981. PMID 6113835. 
  19. ↑ 19.0 19.1 19.2 "Additional studies on side effects of melperone in long-term therapy for 1-20 years in psychiatric patients". Arzneimittel-Forschung 36 (5): 855–60. May 1986. PMID 2873821. 
  20. ↑ "Successful treatment of schizophrenia with melperone augmentation in a patient with phenotypic CYP2D6 ultrarapid metabolization: a case report". Journal of Medical Case Reports 6 (1): 49. February 2012. doi:10.1186/1752-1947-6-49. PMID 22309430. 
  21. ↑ "Cytochrome P450 2D6 dependent metabolization of risperidone is inhibited by melperone". European Journal of Clinical Pharmacology 62 (4): 333–4. April 2006. doi:10.1007/s00228-006-0098-y. PMID 16534635. 
  22. ↑ "Melperone is an inhibitor of the CYP2D6 catalyzed O-demethylation of venlafaxine". Pharmacopsychiatry 36 (1): 3–6. January 2003. doi:10.1055/s-2003-38084. PMID 12649767. 
  23. ↑ "Atypical Antipsychotics: Mechanism of Action". FOCUS: The Journal of Lifelong Learning in Psychiatry 2 (1): 48–58. January 2004. doi:10.1176/foc.2.1.48. PMID 11873706. http://psychiatryonline.org/data/Journals/FOCUS/2601/48.pdf. 
  24. ↑ "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. http://pdsp.med.unc.edu/pdsp.php. 
  25. ↑ J Lassen, S Hernestam, N Sterner, U.S. Patent 3,816,433 (1974 to Ferrosan Ab).
  26. ↑ BE651144 idem Erik Harry Hernestam Sven, et al. GB patent 1029220 (1966 to Ferrosan); CA, 63, 13244c
  27. ↑ Leyva-Pérez, Antonio; Cabrero-Antonino, Jose R.; Rubio-Marqués, Paula; Al-Resayes, Saud I.; Corma, Avelino (2014). "Synthesis of the ortho/meta/para Isomers of Relevant Pharmaceutical Compounds by Coupling a Sonogashira Reaction with a Regioselective Hydration". ACS Catalysis. 4 (3): 722–731. doi:10.1021/cs401075z.

External links



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