Metitepine

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| _other_data=1-methyl-4-(8-methylsulfanyl-5,6-dihydrobenzo[b][1]benzothiepin-6-yl)piperazine

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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.

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. The drug has antipsychotic properties.

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:

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

File: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).

External links

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