Metitepine (; 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 5-HT5A 1.0–32100–12629–146 HumanMouseRat 5-HT5B 1629–145 MouseRat 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
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]benzothiepin-5-one, CID:827052 (6). The reduction with sodium borohydride gives 3-methylsulfanyl-5,6-dihydrobenzo[b]benzothiepin-5-ol, CID:13597048 (7). Halogenating with a second round of thionyl chloride gives 5-chloro-3-methylsulfanyl-5,6-dihydrobenzo[b]benzothiepine, CID:12404411. Alkylation with 1-methylpiperazine [109-01-3] completed the synthesis of Metitepine (9).
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