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melperone

{{Short description|Antipsychotic drug}}

{{Infobox drug

| verifiedrevid = 447616990

| IUPAC_name = 1-(4-fluorophenyl)-4-(4-methylpiperidin-1-yl)butan-1-one

| image = Melperone.svg

| image_class = skin-invert-image

| alt = Skeletal formula of melperone

| width = 250

| image2 = Melperone 3D ball.png

| alt2 = Space-filling model of the melperone molecule

| width2 = 250

| tradename = Buronil

| Drugs.com = {{drugs.com|international|melperone}}

| pregnancy_category =

| legal_status = Rx-only

| routes_of_administration = Oral, intramuscular injection

| bioavailability = 87% (IM), 54% (Oral via syrup), 65% (Oral, tablet){{cite journal | vauthors = Borgström L, Larsson H, Molander L | title = Pharmacokinetics of parenteral and oral melperone in man | journal = European Journal of Clinical Pharmacology | volume = 23 | issue = 2 | pages = 173–6 | year = 1982 | pmid = 7140807 | doi = 10.1007/BF00545974 | s2cid = 36697288 }}

| protein_bound = 50%

| metabolism = Hepatic

| elimination_half-life = 3–4 hours (oral)
6 hours (IM)

| excretion = Renal (70% as metabolites, 5.5–10.4% as unchanged drug)

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 3575-80-2

| ATC_prefix = N05

| ATC_suffix = AD03

| PubChem = 15387

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB09224

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 14646

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = J8WA3K39B7

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D07309

| ChEMBL = 1531134

| C=16 | H=22 | F=1 | N=1 | O=1

| smiles = Fc1ccc(cc1)C(=O)CCCN2CCC(CC2)C

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C16H22FNO/c1-13-8-11-18(12-9-13)10-2-3-16(19)14-4-6-15(17)7-5-14/h4-7,13H,2-3,8-12H2,1H3

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = DKMFBWQBDIGMHM-UHFFFAOYSA-N

}}

Melperone (Bunil (PT), Buronil (AT, BE, CZ, DK, FI†, NL†, NO†, SE), Eunerpan (DE)) 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.

Marketing and indications

It has been tried in treatment-resistant cases of schizophrenia with some (albeit limited) success.{{cite journal | vauthors = Röhricht F, Gadhia S, Alam R, Willis M | title = Auditing clinical outcomes after introducing off-licence prescribing of atypical antipsychotic melperone for patients with treatment refractory schizophrenia | journal = TheScientificWorldJournal | volume = 2012 | pages = 512047 | year = 2012 | pmid = 22566771 | pmc = 3330679 | doi = 10.1100/2012/512047 | doi-access = free }}{{cite journal | vauthors = Whiskey E, Vavrova M, Gaughran F, Taylor D | title = Melperone in treatment-refractory schizophrenia: a case series | journal = Therapeutic Advances in Psychopharmacology | volume = 1 | issue = 1 | pages = 19–23 | date = February 2011 | pmid = 23983923 | pmc = 3736899 | doi = 10.1177/2045125311399800 }}{{cite journal | vauthors = Meltzer HY, Sumiyoshi T, Jayathilake K | title = Melperone in the treatment of neuroleptic-resistant schizophrenia | journal = Psychiatry Research | volume = 105 | issue = 3 | pages = 201–9 | date = December 2001 | pmid = 11814539 | doi = 10.1016/s0165-1781(01)00346-8 | s2cid = 23311317 }}{{cite journal| vauthors = Sumiyoshi T, Meltzer HY, Jayathilake K |title=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|journal=International Clinical Psychopharmacology|year=2004|volume=19|issue=3|page=184|doi=10.1097/00004850-200405000-00039}} It has also been reported effective in the treatment of L-DOPA and other forms of psychosis in Parkinson's diseaseBarbato 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. (although a multicentre, double-blind, placebo-controlled study conducted in 2012 failed to support these findings{{cite journal | vauthors = Friedman JH | title = Melperone is ineffective in treating Parkinson's disease psychosis | journal = Movement Disorders | volume = 27 | issue = 6 | pages = 803–4 | date = May 2012 | pmid = 22362330 | doi = 10.1002/mds.24942 | s2cid = 41211677 }}). It is also known to possess anxiolytic properties.{{cite journal | vauthors = Pöldinger WJ | title = Melperone in low doses in anxious neurotic patients. A double-blind placebo-controlled clinical study | journal = Neuropsychobiology | volume = 11 | issue = 3 | pages = 181–6 | year = 1984 | pmid = 6147789 | doi = 10.1159/000118074 }} It is marketed in the following countries:{{cite book |url=http://www.medicinescomplete.com/mc/martindale/current/11022-r.htm |title=Melperone Hydrochloride |date=30 January 2013 |work=Martindale: The Complete Drug Reference |publisher=The Royal Pharmaceutical Society of Great Britain |access-date=3 November 2013 |archive-date=14 January 2021 |url-status=dead |archive-url=https://web.archive.org/web/20210114165327/https://about.medicinescomplete.com/ }}{{Cite web |title= Buronil generic. Price of buronil. Uses, Dosage, Side effects|url=https://www.ndrugs.com/?s=buronil}}

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Adverse effects

Melperone is reported to produce significantly less weight gain than clozapine and approximately as much weight gain as typical antipsychotics.{{cite journal | vauthors = Bobo WV, Jayathilake K, Lee MA, Meltzer HY | title = Changes in weight and body mass index during treatment with melperone, clozapine and typical neuroleptics | journal = Psychiatry Research | volume = 176 | issue = 2–3 | pages = 114–9 | date = April 2010 | pmid = 20199813 | doi = 10.1016/j.psychres.2009.03.026 | s2cid = 25366120 }} It is also purported to produce around as much prolactin secretion as clozapine (which is virtually nil).{{cite journal | vauthors = Bobo WV, Jayathilake K, Lee MA, Meltzer HY | title = Melperone, an aytpical antipsychotic drug with clozapine-like effect on plasma prolactin: contrast with typical neuroleptics | journal = Human Psychopharmacology | volume = 24 | issue = 5 | pages = 415–22 | date = July 2009 | pmid = 19551763 | doi = 10.1002/hup.1036 | s2cid = 25812368 }} It is also purported to produce sedative effects{{cite journal | vauthors = Molander L, Borgström L | title = Sedative effects and prolactin response to single oral doses of melperone | journal = Psychopharmacology | volume = 79 | issue = 2–3 | pages = 142–7 | year = 1983 | pmid = 6133301 | doi = 10.1007/bf00427801 | s2cid = 392818 }} and QT interval prolongation.{{cite journal | vauthors = Hui WK, Mitchell LB, Kavanagh KM, Gillis AM, Wyse DG, Manyari DE, Duff HJ | title = Melperone: electrophysiologic and antiarrhythmic activity in humans | journal = Journal of Cardiovascular Pharmacology | volume = 15 | issue = 1 | pages = 144–9 | date = January 1990 | pmid = 1688972 | doi = 10.1097/00005344-199001000-00023 | s2cid = 40589560 | doi-access = free }} It is also known to produce less extrapyramidal side effects than the first-generation (typical) antipsychotic, thiothixene.{{cite journal | vauthors = Bjerkenstedt L | title = Melperone in the treatment of schizophrenia | journal = Acta Psychiatrica Scandinavica. Supplementum | volume = 352 | pages = 35–9 | year = 1989 | pmid = 2479227 | doi = 10.1111/j.1600-0447.1989.tb06434.x | s2cid = 7828966 }} It can also produce (usually relatively mild) dry mouth.{{cite journal | vauthors = Molander L, Birkhed D | title = Effect of single oral doses of various neuroleptic drugs on salivary secretion rate, pH, and buffer capacity in healthy subjects | journal = Psychopharmacology | volume = 75 | issue = 2 | pages = 114–8 | year = 1981 | pmid = 6119724 | doi = 10.1007/bf00432171 | s2cid = 780924 }}

;Other common adverse effects include{{cite report |title= Product Information: Eunerpan(R), Melperonhydrochlorid |publisher=Knoll Deutschland GmbH, Ludwigshafen|year=1995}}{{cite journal | vauthors = Kirkegaard A, Kirkegaard G, Geismar L, Christensen I | title = Additional studies on side effects of melperone in long-term therapy for 1 to 15 years in psychiatric patients | journal = Arzneimittel-Forschung | volume = 31 | issue = 4 | pages = 737–40 | year = 1981 | pmid = 6113835 }}{{cite journal | vauthors = Christensen I, Geismar L, Kirkegaard A, Kirkegaard G | title = Additional studies on side effects of melperone in long-term therapy for 1-20 years in psychiatric patients | journal = Arzneimittel-Forschung | volume = 36 | issue = 5 | pages = 855–60 | date = May 1986 | pmid = 2873821 }}

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;Rare adverse effects include

;Unknown frequency adverse effects include

{{div col|colwidth=22em}}

  • 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

{{div col end}}

Interactions

Melperone is reported to be a CYP2D6 inhibitor.{{cite journal | vauthors = Gahr M, Gastl R, Kölle MA, Schönfeldt-Lecuona C, Freudenmann RW | title = Successful treatment of schizophrenia with melperone augmentation in a patient with phenotypic CYP2D6 ultrarapid metabolization: a case report | journal = Journal of Medical Case Reports | volume = 6 | issue = 1 | pages = 49 | date = February 2012 | pmid = 22309430 | pmc = 3298719 | doi = 10.1186/1752-1947-6-49 | doi-access = free }}{{cite journal | vauthors = Köhnke MD, Lutz U, Wiatr G, Schwärzler F, Weller B, Schott K, Buchkremer G | title = Cytochrome P450 2D6 dependent metabolization of risperidone is inhibited by melperone | journal = European Journal of Clinical Pharmacology | volume = 62 | issue = 4 | pages = 333–4 | date = April 2006 | pmid = 16534635 | doi = 10.1007/s00228-006-0098-y | s2cid = 13168439 }}{{cite journal | vauthors = Grözinger M, Dragicevic A, Hiemke C, Shams M, Müller MJ, Härtter S | title = Melperone is an inhibitor of the CYP2D6 catalyzed O-demethylation of venlafaxine | journal = Pharmacopsychiatry | volume = 36 | issue = 1 | pages = 3–6 | date = January 2003 | pmid = 12649767 | doi = 10.1055/s-2003-38084 | s2cid = 260242201 }}

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.{{cite journal|title=Atypical Antipsychotics: Mechanism of Action |date=January 2004 |volume=2 |issue=1 |pages=48–58 | vauthors = Seeman P |url= http://psychiatryonline.org/data/Journals/FOCUS/2601/48.pdf |archive-url= https://web.archive.org/web/20131127043331/http://psychiatryonline.org/data/Journals/FOCUS/2601/48.pdf |url-status= dead |archive-date= 2013-11-27 |journal=FOCUS: The Journal of Lifelong Learning in Psychiatry|doi=10.1176/foc.2.1.48 |pmid=11873706 }}

class="wikitable"
ReceptorKi [nM]{{cite web|title=PDSP Ki Database |work=Psychoactive Drug Screening Program (PDSP)|author1-link=Bryan Roth | vauthors = Roth BL, Driscol J |url=http://pdsp.med.unc.edu/pdsp.php |publisher=University of North Carolina at Chapel Hill and the United States National Institute of Mental Health |access-date=2013-10-14 |url-status=dead |archive-url=https://web.archive.org/web/20131108013656/http://pdsp.med.unc.edu/pdsp.php |archive-date=2013-11-08 }}
5-HT1A2,200
5-HT1D3,400
5-HT2A230
5-HT2C2,100
5-HT61,254
5-HT7578
α1180
α2150
M1>10,000
M22,400
M3>10,000
M44,400
M5>10,000
D2194
D3347
D4555
H1580

Synthesis

File:Melperone_synthesis.svg

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

{{Reflist}}

External links

  • [https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=pcsubstance&term=Melperone, PubChem Substance]
  • {{ClinicalTrialsGov|NCT00125138|Melperone (an Anti-Psychotic) in Patients With Psychosis Associated With Parkinson's Disease}}

{{Antipsychotics}}

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Category:Atypical antipsychotics

Category:4-Fluorophenyl compounds

Category:Piperidines

Category:Butyrophenone antipsychotics

Category:Dopamine antagonists

Category:Serotonin receptor antagonists

Category:Alpha-1 blockers

Category:Alpha-2 blockers