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).