Due to its very potent activity at the D2 receptor, along with tefludazine, clorotepine was used as the basis for developing a 3-dimensional (3D) pharmacophore for D2 receptor antagonists.[14]
Synthesis
Synthesis:
The first step involves an Ullmann condensation between 2-iodophenylacetic acid [18698-96-9] (1) and 4-chlorothiophenol [106-54-7] (2) to give [13459-62-6] (3). Ring closure by heating in PPA gives 8-chlorodibenzo[b,f]thiepin-10(11H)-one [1469-28-9] (4). The modern method first forms the enamine in 99% yield. Reduction of this with NaBH4 in the presence of acid afforded clorotepine in 80% yield. The acid is needed to shift the stable enamine tautomer into the iminium salt quaternary cation, which is vulnerable to attack from the incoming hydride nucleophile. Thus, the classical method (i.e. ketone to ROH to leaving group) might not be needed anymore.
Amoxapine, sold under the brand name Asendin among others, is a tricyclic antidepressant (TCAs). It is the N-demethylated metabolite of loxapine. Amoxapine first received marketing approval in the United States in 1992.
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Dopamine receptor D1, also known as DRD1. It is one of the two types of D1-like receptor family - receptors D1 and D5. It is a protein that in humans is encoded by the DRD1 gene.
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Tiospirone (BMY-13,859), also sometimes called tiaspirone or tiosperone, is an atypical antipsychotic of the azapirone class. It was investigated as a treatment for schizophrenia in the late 1980s and was found to have an effectiveness equivalent to those of typical antipsychotics in clinical trials but without causing extrapyramidal side effects. However, development was halted and it was not marketed. Perospirone, another azapirone derivative with antipsychotic properties, was synthesized and assayed several years after tiospirone. It was found to be both more potent and more selective in comparison and was commercialized instead.
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SB-206553 is a drug which acts as a mixed antagonist for the 5-HT2B and 5-HT2C serotonin receptors. It has anxiolytic properties in animal studies and interacts with a range of other drugs. It has also been shown to act as a positive allosteric modulator of α7 nicotinic acetylcholine receptors. Modified derivatives of SB-206553 have been used to probe the structure of the 5-HT2B receptor.
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↑ Metysová J, Metys J, Dlabac A, Kazdová E, Valchár M (1980). "Pharmacological properties of a potent neuroleptic drug octoclothepin". Acta Biologica et Medica Germanica. 39 (6): 723–40. PMID6893891.
1 2 Bøgesø KP, Liljefors T, Arnt J, Hyttel J, Pedersen H (July 1991). "Octoclothepin enantiomers. A reinvestigation of their biochemical and pharmacological activity in relation to a new receptor-interaction model for dopamine D-2 receptor antagonists". Journal of Medicinal Chemistry. 34 (7): 2023–30. doi:10.1021/jm00111a015. PMID1676758.
1 2 3 Kristensen JL, Püschl A, Jensen M, etal. (October 2010). "Exploring the neuroleptic substituent in octoclothepin: potential ligands for positron emission tomography with subnanomolar affinity for α(1)-adrenoceptors". Journal of Medicinal Chemistry. 53 (19): 7021–34. doi:10.1021/jm100652h. PMID20857909.
↑ Liljefors T, Bøgesø KP (February 1988). "Conformational analysis and structural comparisons of (1R,3S)-(+)- and (1S,3R)-(−)-tefludazine, (S)-(+)- and (R)-(−)-octoclothepin, and (+)-dexclamol in relation to dopamine receptor antagonism and amine-uptake inhibition". Journal of Medicinal Chemistry. 31 (2): 306–12. doi:10.1021/jm00397a006. PMID2892932.
↑ Protiva M, Jílek JO, Metysová J, et al. Neurotropic and psychotropic agents. 8. 10-(4-Methylpiperazion)-10,11-dihydrodibenzo(b,f)thiepine and analogs; a new group of potent neuroleptics. (Preliminary communication). Farmaco Sci. 1965;20(10):721-5. PMID: 5882350.
↑ Jílek, Jiří O.; Pomykáček, Josef; Metyšová, Jiřina; Bartošová, Marie; Protiva, Miroslav (1978). "Potential metabolites of the neuroleptic agent octoclothepin; Synthesis and pharmacology of 8-chloro-6-hydroxy-10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepin and some related compounds". Collection of Czechoslovak Chemical Communications. 43 (7): 1747–1759. doi:10.1135/cccc19781747.
↑ Jílek, Jiří; Pomykáček, Josef; Prošek, Zdeněk; Holubek, Jiří; Svátek, Emil; Metyšová, Jiřina; Dlabač, Antonín; Protiva, Miroslav (1983). "8-Chloro and 8-methylthio derivatives of 10-piperazino-10,11-dihydrodibenzo[b,f]thiepins; New compounds and new procedures". Collection of Czechoslovak Chemical Communications. 48 (3): 906–927. doi:10.1135/cccc19830906.
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