Metitepine

Metitepine (INNTooltip 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]

Metitepine

Clinical data
Other names	Methiothepin; Methiothepine; Ro 8-6837 (maleate); VUFB-6276 (mesylate)
Identifiers
IUPAC name 1-methyl-4-(8-methylsulfanyl-5,6-dihydrobenzo[b][1]benzothiepin-6-yl)piperazine
CAS Number	20229-30-5 19728-88-2 (maleate)
PubChem CID	4106
IUPHAR/BPS	89
ChemSpider	3963
UNII	55D94103HL
ChEBI	CHEBI:64203
CompTox Dashboard (EPA)	DTXSID2044000
ECHA InfoCard	100.261.496
Chemical and physical data
Formula	C20H24N2S2
Molar mass	356.55 g·mol−1
3D model (JSmol)	Interactive image
SMILES CN1CCN(CC1)C2Cc3ccccc3Sc4c2cc(cc4)SC
InChI 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

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	2.2–631	Human
5-HT1B	0.2–40	Human
5-HT1D	5.8–170	Human
5-HT1E	120–209	Human
5-HT1F	646–652	Human
5-HT2A	0.1–3.2	Human
5-HT2B	0.58–2.1	Human
5-HT2C	0.34–4.5	Human
5-HT3	≥3,000	Rat
5-HT4	ND	ND
5-HT5A	1.0–32 100–126 29–146	Human Mouse Rat
5-HT5B	16 29–145	Mouse Rat
5-HT6	0.30–4.1	Human
5-HT7	0.4–4.0	Human
α1A	0.06–7.9	Guinea pig
α1B	0.5	Pig
D1	2.0	Rat
D2	0.40	Rat
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:^[8][9][10]

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. Roth BL, Driscol J. "PDSP K_i 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. 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.

External links

• Methiothepin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)