Melperone

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. 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). It is also known to possess anxiolytic properties. It is marketed in the following countries:

Austria Czech Republic Denmark Estonia Finland Germany Iceland Lithuania Latvia Portugal Sweden

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

Other common adverse effects include

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 Tardive dyskinesia Neuroleptic malignant syndrome Blood dyscrasias (pancytopenia, agranulocytosis, leukopenia, thrombocytopenia, etc.)

Unknown frequency adverse effects include

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.

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. Receptor Ki [nM] 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

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).

Melperone

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