Zotepine

Zotepine
Clinical data
Trade namesZoleptil
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • BR: Class C1 (Other controlled substances)[1]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability7–13% (oral)[2]
MetabolismN-desmethylation to norzotepine (30-40%)[2]
Elimination half-life13.7–15.9 hours, 12 hours (Norzotepine)[2]
Excretion17% (Urine)[2]
Identifiers
  • 2-(3-chlorobenzo[b][1]benzothiepin-5-yl)oxy-N,N-dimethylethanamine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.189.143 Edit this at Wikidata
Chemical and physical data
FormulaC18H18ClNOS
Molar mass331.86 g·mol−1
3D model (JSmol)
  • Clc2cc1C(/OCCN(C)C)=C\c3c(Sc1cc2)cccc3
  • 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 checkY
  • Key:HDOZVRUNCMBHFH-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

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]
Unknown frequency[2][4]
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-HT2A, 5-HT2C, 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

References

  1. ^ 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.
  2. ^ a b c d e f g Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Jun 25]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  3. ^ a b "Zotepine". Martindale: The Complete Drug Reference. Royal Pharmaceutical Society of Great Britain. 16 August 2013. Retrieved 2 November 2013.
  4. ^ a b c d British National Formulary 58. British Medical Association and Royal Pharmaceutical Society of Great Britain; 2009.
  5. ^ 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.
  6. ^ Harada T, Otsuki S (1986). "Antimanic effect of zotepine". Clinical Therapeutics. 8 (4): 406–14. PMID 3089626.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ "Zotepine". Pharmaceutical Substances. Thieme. Retrieved 2024-07-10.

Further reading