Zotepine

Zotepine is an atypical antipsychotic drug indicated for acute and chronic schizophrenia. It has been used in Germany since 1990 (although it has been discontinued in Germany) and Japan since 1982.

Zotepine

Clinical data
Trade names	Zoleptil
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral
ATC code	N05AX11 (WHO)
Legal status
Legal status	BR: Class C1 (Other controlled substances)[1] In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	7–13% (oral)[2]
Metabolism	N-desmethylation to norzotepine (30-40%)[2]
Elimination half-life	13.7–15.9 hours, 12 hours (Norzotepine)[2]
Excretion	17% (Urine)[2]
Identifiers
IUPAC name 2-(3-chlorobenzo[b][1]benzothiepin-5-yl)oxy-N,N-dimethylethanamine
CAS Number	26615-21-4 N
PubChem CID	5736
IUPHAR/BPS	103
DrugBank	DB09225 N
ChemSpider	5534 Y
UNII	U29O83JAZW
KEGG	D01321 Y
ChEBI	CHEBI:32316 Y
ChEMBL	ChEMBL285802 Y
PDB ligand	ZOT (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID9023756
ECHA InfoCard	100.189.143
Chemical and physical data
Formula	C18H18ClNOS
Molar mass	331.86 g·mol−1
3D model (JSmol)	Interactive image
SMILES Clc2cc1C(/OCCN(C)C)=C\c3c(Sc1cc2)cccc3
InChI InChI=1S/C18H18ClNOS/c1-20(2)9-10-21-16-11-13-5-3-4-6-17(13)22-18-8-7-14(19)12-15(16)18/h3-8,11-12H,9-10H2,1-2H3 Y Key:HDOZVRUNCMBHFH-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

Zotepine is not approved for use in the United States, United Kingdom, Australia, Canada or New Zealand.^[3]

Medical uses

Zotepine's primary use is as a treatment for schizophrenia^[4] although clinical trials have been conducted (with positive results) into its efficacy as an antimanic agent in patients with acute bipolar mania.^[5][6][7] In a 2013 study in a comparison of 15 antipsychotic drugs in effectivity in treating schizophrenic symptoms, zotepine demonstrated medium-strong effectivity. Less effective than clozapine, slightly less effective than olanzapine and risperidone, approximately as effective as paliperidone, and slightly more effective than haloperidol, quetiapine, and aripiprazole.^[8]

Side effects

Common^[2][4]

• Tachycardia
• Hypotension
• Orthostatic hypotension
• Palpitations
• Hyperprolactinaemia
• Weight gain (produces a similar degree of weight gain to that seen with clozapine and olanzapine treatment)^[9]
• Somnolence (2nd highest effect size for causing sedation out of fifteen antipsychotics compared in a recent meta-analysis)^[9]
• Extrapyramidal side effects [EPSE] (2nd largest odds ratio for causing EPSE out of fifteen antipsychotics compared in a recent meta-analysis, second only to haloperidol)^[9]
• Constipation
• Xerostomia (dry mouth)
• Blurred vision
• Hypersalivation (drooling)
• Mydriasis
• Anxiety
• Agitation
• Rhinitis
• Sexual dysfunction
• Dyspnoea
• Diarrhoea
• Influenza-like symptoms
• Cough
• Vertigo
• Confusion
• Dyspepsia
• Flushing dry skin
• Arthralgia
• Myalgia
• Acne
• Conjunctivitis
• Thrombocythaemia

Unknown frequency^[2][4]

• QT interval prolongation
• Hyperthermia
• Hypothermia
• Increased serum creatinine
• Hyperglycaemia
• Hypoglycaemia
• Hyperlipidaemia
• Thirst
• Urinary incontinence

Rare^[2][4]

• Angle-closure glaucoma
• Agranulocytosis
• Neutropaenia
• Eosinophilia
• Leukocytopenia
• Hypoesthesia
• Anaemia
• Myoclonus
• Myasthenia
• Alopecia
• Thrombocytopaenia
• Bradycardia
• Epistaxis
• Abdominal enlargement
• Deep vein thrombosis
• Paralytic ileus
• Leukopenia
• Tardive dyskinesia
• Neuroleptic malignant syndrome
• Laryngeal edema
• Urinary retention
• Depression
• Ataxia
• Amnesia
• Seizure (dose-dependent risk)^[3]
• Metabolic syndrome
• Diabetes mellitus type II
• Cholestasis
• Increased liver enzymes
• Photosensitivity
• Exanthema
• Pruritus
• Hypouricemia
• Oedema

Pharmacology

Pharmacodynamics

The antipsychotic effect of zotepine is thought to be mediated through antagonist activity at dopamine and serotonin receptors. Zotepine has a high affinity for the D₁ and D₂ receptors. It also affects the 5-HT_2A, 5-HT_2C, 5-HT₆, and 5-HT₇ receptors.^[10] In addition, its active metabolite, norzotepine, serves as a potent norepinephrine reuptake inhibitor.^[11]

Macromolecule (Receptor or transporter protein)	Ki [nM][10]
SERT	151
NET	530
DAT	3621
5-HT1A	470.5
5-HT1B	59.5
5-HT1D	119
5-HT1E	700
5-HT2A	2.7
5-HT2C	2.6
5-HT3	472
5-HT5A	29
5-HT6	6
5-HT7	12
α1A	7
α1B	5
α2A	180
α2B	5.35
α2C	106
M1	18
M2	140
M3	73
M4	77
M5	260
D1	71
D2	25
D2S	5.4
D2L	11
D3	6.4
D4	18
D5	248
H1	3.21
H2	500
H4	1977

Synthesis

The reaction of 2-chloroacetophenone with 4-chlorothiophenol gives a thioether. This is treated with morpholine and sulfur in a Willgerodt–Kindler reaction to give a phenylacetic acid derivative after acid hydrolysis of the amide intermediate. Cyclization of this compound in the presence of polyphosphoric acid forms the dibenzothiepin ring system of the drug. The enol ether, zotepine, is produced when this is treated with the chloroethyl amine and potassium carbonate in methyl isobutyl ketone as solvent. Under these conditions, the undesired product of C-alkylation is minimised.^[12][13][14]

Society and culture

Brand names

Brand names include Losizopilon (JP), Lodopin (ID, JP), Setous (JP), Zoleptil (CZ, PT, TR, UK†), Zotewin (IN); where † indicates a formulation that has been discontinued.

See also

• Carbinoxamine, diphenhydramine, doxylamine, orphenadrine — the termination chain is the same
• Clotiapine - the base is similar
• Noxiptyline - the termination chain is similar
• Toll-like receptor 4 — investigating probable antagonistic (antiinflammatory) property of several TCA-based molecules