Clorotepine

{{Short description|Antipsychotic medication}}

{{cs1 config|name-list-style=vanc}}

{{Drugbox

| IUPAC_name = 1-(8-chloro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-4-methylpiperazine

| image = Clorotepine.svg

| width = 225px

| tradename = Clotepin, Clopiben

| CAS_number = 13448-22-1

| CAS_supplemental =
4789-68-8 (maleate)
42505-79-3 (mesylate)

| ATC_prefix = None

| ATC_suffix =

| UNII = E65W20MU7A

| PubChem = 1238

| ChemSpiderID = 1201

| ChEMBL = 64249

| C = 19 | H = 21 | Cl = 1 | N = 2 | S = 1

| SMILES = Clc4cc2c(Sc1ccccc1CC2N3CCN(C)CC3)cc4

| synonyms = Octoclothepin; Octoclothepine; VUFB-6281; VUFB-10030

| StdInChI = 1S/C19H21ClN2S/c1-21-8-10-22(11-9-21)17-12-14-4-2-3-5-18(14)23-19-7-6-15(20)13-16(17)19/h2-7,13,17H,8-12H2,1H3

| StdInChIKey = XRYLGRGAWQSVQW-UHFFFAOYSA-N

| bioavailability =

| protein_bound =

| metabolism =

| elimination_half-life =

| excretion =

| pregnancy_category =

| legal_status = Rx-only

| routes_of_administration = By mouth

}}

Clorotepine ({{abbrlink|INN|International Nonproprietary Name}}; brand names Clotepin, Clopiben), also known as octoclothepin or octoclothepine, is an antipsychotic of the tricyclic group which was derived from perathiepin in 1965 and marketed in the Czech Republic by Spofa in or around 1971 for the treatment of schizophrenic psychosis.{{cite book | title = Index nominum 2000: international drug directory | url = https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA265 | access-date = 26 November 2011 | year = 2000 | publisher = Taylor & Francis US | isbn = 978-3-88763-075-1 | pages = 265}}{{cite book | vauthors = Ganellin CR, Triggle DJ, Macdonald F | title = Dictionary of pharmacological agents | url = https://books.google.com/books?id=DeX7jgInYFMC&pg=PA500 | access-date = 26 November 2011 | year = 1997 | publisher = CRC Press | isbn = 978-0-412-46630-4 | pages = 500}}{{cite journal |vauthors=Metysová J, Metys J, Dlabac A, Kazdová E, Valchár M | title = Pharmacological properties of a potent neuroleptic drug octoclothepin | journal = Acta Biologica et Medica Germanica | volume = 39 | issue = 6 | pages = 723–40 | year = 1980 | pmid = 6893891 }}{{cite book | vauthors = Cain CK | title = Annual Reports in Medicinal Chemistry | url = https://books.google.com/books?id=dBGM4WSV_YEC&pg=PA5 | access-date = 26 November 2011 | date = 1 January 1971 | publisher = Academic Press | isbn = 978-0-12-040506-0 | pages = 5}}{{cite journal| vauthors = Protiva M |title=ChemInform Abstract: Fifty Years in Chemical Drug Research|journal=ChemInform|volume=23|issue=9|year=2010|pages=no|issn=0931-7597|doi=10.1002/chin.199209338}}{{cite journal | vauthors = Melich H | title = [Clotepin] | language = cs | journal = Cas. Lek. Cesk. | volume = 110 | issue = 17 | pages = 404–5 | year = 1971 | pmid = 5576292 }}

Clorotepine is known to have high affinity for the dopamine D₁,{{cite journal |vauthors=Campiani G, Butini S, Gemma S | title = Pyrrolo[1,3]benzothiazepine-based atypical antipsychotic agents. Synthesis, structure-activity relationship, molecular modeling, and biological studies | journal = Journal of Medicinal Chemistry | volume = 45 | issue = 2 | pages = 344–59 |date=January 2002 | pmid = 11784139 | doi = 10.1021/jm010982y|display-authors=etal}} D₂,{{cite journal |vauthors=Burstein ES, Ma J, Wong S | title = Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 315 | issue = 3 | pages = 1278–87 |date=December 2005 | pmid = 16135699 | doi = 10.1124/jpet.105.092155 | s2cid = 2247093 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16135699|display-authors=etal}} D₃, and D₄ receptors, the serotonin 5-HT_2A, 5-HT_2B,{{cite journal |vauthors=Bøgesø KP, Liljefors T, Arnt J, Hyttel J, Pedersen H | title = 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 = Journal of Medicinal Chemistry | volume = 34 | issue = 7 | pages = 2023–30 |date=July 1991 | pmid = 1676758 | doi = 10.1021/jm00111a015}} 5-HT_2C, 5-HT₆,{{cite journal|author1-link=Bryan Roth |vauthors=Roth BL, Craigo SC, Choudhary MS | title = Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 268 | issue = 3 | pages = 1403–10 |date=March 1994 | pmid = 7908055 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7908055|display-authors=etal}} and 5-HT₇ receptors, the α_1A-,{{cite journal |vauthors=Kristensen JL, Püschl A, Jensen M | title = Exploring the neuroleptic substituent in octoclothepin: potential ligands for positron emission tomography with subnanomolar affinity for α(1)-adrenoceptors | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 19 | pages = 7021–34 |date=October 2010 | pmid = 20857909 | doi = 10.1021/jm100652h |display-authors=etal}} α_1B-, and α_1D-adrenergic receptors, and the histamine H₁ receptors,{{cite journal |vauthors=Lim HD, van Rijn RM, Ling P, Bakker RA, Thurmond RL, Leurs R | title = Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 314 | issue = 3 | pages = 1310–21 |date=September 2005 | pmid = 15947036 | doi = 10.1124/jpet.105.087965 | s2cid = 24248896 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15947036}} where it has been it has been confirmed to act as an antagonist (or inverse agonist) at most sites (and likely is as such at all of them based on structure–activity relationships), and it also blocks the reuptake of norepinephrine via inhibition of the norepinephrine transporter.{{cite journal |vauthors=Liljefors T, Bøgesø KP | title = 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 = Journal of Medicinal Chemistry | volume = 31 | issue = 2 | pages = 306–12 |date=February 1988 | pmid = 2892932 | doi = 10.1021/jm00397a006}}

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.{{cite book | vauthors = Krogsgaard-Larsen P, Liljefors T, Madsen U | title = Textbook of drug design and discovery | url = https://books.google.com/books?id=EL-UI6t8omQC&pg=PA108 | access-date = 26 November 2011 | date = 25 July 2002 | publisher = CRC Press | isbn = 978-0-415-28288-8 | page = 108}}