Zotepine

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); In general: ℞ (Prescription only);
Pharmacokinetic data
Bioavailability	7–13% (oral)
Metabolism	N-desmethylation to norzotepine (30-40%)
Elimination half-life	13.7–15.9 hours, 12 hours (Norzotepine)
Excretion	17% (Urine)
Identifiers
	IUPAC name 2-(3-chlorobenzo[b][1]benzothiepin-5-yl)oxy-N,N-dimethylethanamine;
CAS Number	26615-21-4 ;
PubChem CID	5736;
IUPHAR/BPS	103;
DrugBank	DB09225 ;
ChemSpider	5534 ;
UNII	U29O83JAZW;
KEGG	D01321 ;
ChEBI	CHEBI:32316 ;
ChEMBL	ChEMBL285802 ;
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 ; Key:HDOZVRUNCMBHFH-UHFFFAOYSA-N ;
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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 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]

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)	K_i [nM]^[10]
SERT	151
NET	530
DAT	3621
5-HT_1A	470.5
5-HT_1B	59.5
5-HT_1D	119
5-HT_1E	700
5-HT_2A	2.7
5-HT_2C	2.6
5-HT₃	472
5-HT_5A	29
5-HT₆	6
5-HT₇	12
α_1A	7
α_1B	5
α_2A	180
α_2B	5.35
α_2C	106
M₁	18
M₂	140
M₃	73
M₄	77
M₅	260
D₁	71
D₂	25
D_2S	5.4
D_2L	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.

References

^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
^ ^a ^b ^c ^d ^e ^f ^g Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Jun 25]. Greenwood Village, CO: Thomsen Healthcare; 2013.
^ ^a ^b "Zotepine". Martindale: The Complete Drug Reference. Royal Pharmaceutical Society of Great Britain. 16 August 2013. Retrieved 2 November 2013.
^ ^a ^b ^c ^d British National Formulary 58. British Medical Association and Royal Pharmaceutical Society of Great Britain; 2009.
^ Chan HY, Jou SH, Juang YY, Chang CJ, Chen JJ, Chen CH, et al. (April 2010). "A single-blind, comparative study of zotepine versus haloperidol in combination with a mood stabilizer for patients with moderate-to-severe mania". Psychiatry and Clinical Neurosciences. 64 (2): 162–9. doi:10.1111/j.1440-1819.2010.02066.x. PMID 20447012. S2CID 27657241.
^ Harada T, Otsuki S (1986). "Antimanic effect of zotepine". Clinical Therapeutics. 8 (4): 406–14. PMID 3089626.
^ Amann B, Sterr A, Mergl R, Dittmann S, Seemüller F, Dobmeier M, et al. (October 2005). "Zotepine loading in acute and severely manic patients: a pilot study". Bipolar Disorders. 7 (5): 471–6. doi:10.1111/j.1399-5618.2005.00241.x. PMID 16176441.
^ Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, et al. (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet. 382 (9896): 951–62. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. S2CID 32085212.
^ ^a ^b ^c Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, et al. (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet. 382 (9896): 951–62. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. S2CID 32085212.
^ ^a ^b National Institute of Mental Health (12 January 2011). "PDSD Ki Database". Chapel Hill (NC): University of North Carolina. Archived from the original on November 8, 2013. Retrieved 2 November 2013.
^ Shobo M, Kondo Y, Yamada H, Mihara T, Yamamoto N, Katsuoka M, et al. (June 2010). "Norzotepine, a major metabolite of zotepine, exerts atypical antipsychotic-like and antidepressant-like actions through its potent inhibition of norepinephrine reuptake". The Journal of Pharmacology and Experimental Therapeutics. 333 (3): 772–81. doi:10.1124/jpet.110.166264. PMID 20223878. S2CID 185592.
^ Ueda I, Sato Y, Maeno S, Umio S (October 1975). "The synthesis of 10-(4-methylpiperazino)dibenzo (b,f)thiepin and related compounds. Neurotropic and psychotropic agents". Chemical & Pharmaceutical Bulletin. 23 (10): 2223–2231. doi:10.1248/cpb.23.2223. PMID 1212752.
^ Ueda I, Sato Y, Maeno S, Umio S (October 1978). "Synthesis and pharmacological properties of 8-chloro-10-(2-dimethylaminoethoxy)dibenzo[b,f]thiepin and related compounds. Neurotropic and psychotropic agents. III". Chemical & Pharmaceutical Bulletin. 26 (10): 3058–3070. doi:10.1248/cpb.26.3058. PMID 31984.
^ "Zotepine". Pharmaceutical Substances. Thieme. Retrieved 2024-07-10.