Metitepine

Last updated
Metitepine
Metitepine.svg
Clinical data
Other namesMethiothepin; Methiothepine; Ro 8-6837 (maleate); VUFB-6276 (mesylate)
Identifiers
  • 1-methyl-4-(8-methylsulfanyl-5,6-dihydrobenzo[b][1]benzothiepin-6-yl)piperazine
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard 100.261.496 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H24N2S2
Molar mass 356.55 g·mol−1
3D model (JSmol)
  • CN1CCN(CC1)C2Cc3ccccc3Sc4c2cc(cc4)SC
  • InChI=1S/C20H24N2S2/c1-21-9-11-22(12-10-21)18-13-15-5-3-4-6-19(15)24-20-8-7-16(23-2)14-17(18)20/h3-8,14,18H,9-13H2,1-2H3
  • Key:RLJFTICUTYVZDG-UHFFFAOYSA-N

Metitepine (INN Tooltip International Nonproprietary Name; developmental code names Ro 8-6837 (maleate), VUFB-6276 (mesylate)), also known as methiothepin, is a drug described as a "psychotropic agent" of the tricyclic or tetracyclic group which was never marketed. [1]

Contents

It acts as a non-selective antagonist of serotonin, dopamine, and adrenergic receptors, including of the serotonin 5-HT1, 5-HT2, 5-HT5, 5-HT6, and 5-HT7 receptors. [2] [3] [4] [5] [6] The drug has antipsychotic properties. [7]

Pharmacology

Pharmacodynamics

Metitepine binding profile
Target Affinity (Ki, nM)Species
5-HT1A 2.2–631Human
5-HT1B 0.2–40Human
5-HT1D 5.8–170Human
5-HT1E 120–209Human
5-HT1F 646–652Human
5-HT2A 0.1–3.2Human
5-HT2B 0.58–2.1Human
5-HT2C 0.34–4.5Human
5-HT3 ≥3,000Rat
5-HT4 NDND
5-HT5A 1.0–32
100–126
29–146		Human
Mouse
Rat
5-HT5B 16
29–145		Mouse
Rat
5-HT6 0.30–4.1Human
5-HT7 0.4–4.0Human
α1A 0.06–7.9Guinea pig
α1B 0.5Pig
D1 2.0Rat
D2 0.40Rat
Notes: The lower the affinity value, the more avidly the drug binds to the site. Refs: [2] [3]

Chemistry

Analogues

Metitepine is closely structurally related to certain other tetracyclic compounds including amoxapine, batelapine, clorotepine, clotiapine, clozapine, flumezapine, fluperlapine, loxapine, metiapine, olanzapine, oxyprothepin, perathiepin, perlapine, quetiapine, tampramine, and tenilapine.

Synthesis

Synthesis: Metitepine synthesis.svg
Synthesis:

The reduction of 2-(4-methylsulfanylphenyl)sulfanylbenzoic acid, CID:2733664 (1) gives [2-(4-methylsulfanylphenyl)sulfanylphenyl]methanol, CID:12853582 (2). Halogenating with thionyl chloride gives 1-(chloromethyl)-2-(4-methylsulfanylphenyl)sulfanylbenzene, CID:12853583 (3). FGI with cyanide gives 2-[2-(4-methylsulfanylphenyl)sulfanylphenyl]acetonitrile, CID:12853584 (4). Alkali hydrolysis of the nitrile to 2-[2-(4-methylsulfanylphenyl)sulfanylphenyl]acetic acid, CID:12383832 (5). PPA cyclization to 3-methylsulfanyl-6H-benzo[b][1]benzothiepin-5-one, CID:827052 (6). The reduction with sodium borohydride gives 3-methylsulfanyl-5,6-dihydrobenzo[b][1]benzothiepin-5-ol, CID:13597048 (7). Halogenating with a second round of thionyl chloride gives 5-chloro-3-methylsulfanyl-5,6-dihydrobenzo[b][1]benzothiepine, CID:12404411. Alkylation with 1-methylpiperazine [109-01-3] completed the synthesis of Metitepine (9).

References

  1. ↑ J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 815–. ISBN   978-1-4757-2085-3.
  2. 1 2 Roth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  3. 1 2 Liu, Tiqing. "BindingDB BDBM78940 METHIOTHEPIN::MLS000859918::Methiothepin mesylate salt::SMR000326779::cid_3039995::mesylic acid;1-methyl-4-[3-(methylthio)-5,6-dihydrobenzo[b][1]benzothiepin-5-yl]piperazine::methanesulfonic acid;1-methyl-4-(3-methylsulfanyl-5,6-dihydrobenzo[b][1]benzothiepin-5-yl)piperazine::methanesulfonic acid;1-methyl-4-[3-(methylthio)-5,6-dihydrobenzo[b][1]benzothiepin-5-yl]piperazine". BindingDB. Retrieved 1 November 2024.
  4. ↑ Monachon MA, Burkard WP, Jalfre M, Haefely W (1972). "Blockade of central 5-hydroxytryptamine receptors by methiothepin". Naunyn-Schmiedeberg's Arch. Pharmacol. 274 (2): 192–7. doi:10.1007/BF00501854. PMID   4340797. S2CID   19577535.
  5. ↑ Dall'Olio R, Vaccheri A, Montanaro N (1985). "Reduced head-twitch response to quipazine of rats previously treated with methiothepin: possible involvement of dopaminergic system". Pharmacol. Biochem. Behav. 23 (1): 43–8. doi:10.1016/0091-3057(85)90128-5. PMID   2994121. S2CID   29894323.
  6. ↑ Chapman ME, Wideman RF (April 2006). "Evaluation of the serotonin receptor blockers ketanserin and methiothepin on the pulmonary hypertensive responses of broilers to intravenously infused serotonin". Poult Sci. 85 (4): 777–86. doi: 10.1093/ps/85.4.777 . PMID   16615363.
  7. ↑ Lemke TL, Williams DA (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 388–. ISBN   978-1-60913-345-0.
  8. ↑ Jílek JO, Metyšová J, Svátek E, Jančik F, Pomykáček J, Protiva M (1973). "Neurotropic and psychotropic agents. LVI. Sulfoxides, N-oxides and sulfones derived from neuroleptic 10-piperazino-10, 11-dihydrodibenzo [b, f] thiepins". Collection of Czechoslovak Chemical Communications. 38 (2): 599–610. doi:10.1135/cccc19730599.
  9. ↑ Jílek J, Pomykáček J, Dlabač A, Bartošová M, Protiva M (1980). "Neuroleptics of the 8-methylthio-10-piperazino-10, 11-dihydrodibenzo [b, f] thiepin series: New compounds and new procedures". Collection of Czechoslovak Chemical Communications. 45 (2): 504–516. doi:10.1135/cccc19800504.
  10. ↑ Pelz K, Jirkovsky L, Adlerova E, Metysova J, Protiva M (1968). "Über die in 8-Stellung durch die Methyl-, tert. Butyl-, Methoxy-, Methylthio-und Methansulfonylgruppe substituierten 10-(4-Methylpiperazino)-10,11-dihydrodibenzo [b, f] thiepin-Derivate". Collection of Czechoslovak Chemical Communications. 33: 1895–1910. doi:10.1135/cccc19681895.
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