{{Short description|Chemical compound}} {{Drugbox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 437152684 | IUPAC_name = 1-[2-[(4-Chlorophenyl)-phenyl-methoxy]ethyl]piperidine | image = Cloperastine.png | image_class = skin-invert-image
<!--Clinical data-->| caption = Cloperastine structure (above); (S)-cloperastine 3D molecule (below) | image2 = Levocloperastine.png | image_class2 = bg-transparent | tradename = | Drugs.com = {{drugs.com|international|cloperastine}} | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_US = <!-- A / B / C / D / X --> | pregnancy_category = | legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> | legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> | legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> | legal_status = | routes_of_administration = Oral
<!--Pharmacokinetic data-->| bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = <!--Identifiers--> | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 3703-76-2 | ATC_prefix = R05 | ATC_suffix = DB21 | PubChem = 2805 | DrugBank_Ref = {{drugbankcite|changed|drugbank}} | DrugBank = DB09002 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 2703 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 69M5L7BXEK | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D03557 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 415087
<!--Chemical data-->| C = 20 | H = 24 | Cl = 1 | N = 1 | O = 1 | smiles = Clc1ccc(cc1)C(OCCN2CCCCC2)c3ccccc3 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C20H24ClNO/c21-19-11-9-18(10-12-19)20(17-7-3-1-4-8-17)23-16-15-22-13-5-2-6-14-22/h1,3-4,7-12,20H,2,5-6,13-16H2 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = FLNXBVJLPJNOSI-UHFFFAOYSA-N | synonyms = HT-11 }}
'''Cloperastine''' (INN) or '''cloperastin''', in the forms of '''cloperastine hydrochloride''' (JAN) (brand names '''Hustazol''', '''Nitossil''', '''Seki''') and '''cloperastine fendizoate''', is an antitussive and antihistamine that is marketed as a cough suppressant in Japan, Hong Kong, Brazil and in some European countries.<ref name="Elks2014">{{cite book | vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies |url= https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA301 |date=14 November 2014 |publisher=Springer|pages=301– |isbn=978-1-4757-2085-3 }}</ref><ref>{{cite book | editor = Swiss Pharmaceutial Society |title=Index Nominum 2000: International Drug Directory |url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA261 |date=January 2000 |publisher=Taylor & Francis |isbn=978-3-88763-075-1 |pages=261– }}</ref><ref name="CuzzocreaCatania2011">{{cite journal | vauthors = Catania MA, Cuzzocrea S | title = Pharmacological and clinical overview of cloperastine in treatment of cough | journal = Therapeutics and Clinical Risk Management | volume = 7 | pages = 83–92 | year = 2011 | pmid = 21445282 | pmc = 3061847 | doi = 10.2147/TCRM.S16643 | doi-access = free }}</ref> It was first introduced in 1972 in Japan, and then in Italy in 1981.<ref name="Publishing2013">{{cite book |author = William Andrew Publishing |title=Pharmaceutical Manufacturing Encyclopedia |url= https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1103 |date=22 October 2013 |publisher=Elsevier |isbn=978-0-8155-1856-3 |pages=1103– }}</ref>
==Side effects== Adverse effects may include sedation, drowsiness, heartburn, and thickening of bronchial secretions.<ref>{{cite book |isbn=0-8103-7177-4 |title=Drugs Available Abroad, 1st Edition |page=29 |date=1991 | vauthors = Schlesser JL |publisher=Derwent Publications Ltd.}}</ref>
==Pharmacology== The precise mechanism of action of cloperastine is not fully clear, but several different biological activities have been identified for the drug, of which include: ligand of the σ<sub>1</sub> receptor (K<sub>i</sub> = 20 nM) (likely an agonist),<ref name="Gregori-PuigjaneSetola2012">{{cite journal | vauthors = Gregori-Puigjané E, Setola V, Hert J, Crews BA, Irwin JJ, Lounkine E, Marnett L, Roth BL, Shoichet BK | display-authors = 6 | title = Identifying mechanism-of-action targets for drugs and probes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 28 | pages = 11178–83 | date = July 2012 | pmid = 22711801 | pmc = 3396511 | doi = 10.1073/pnas.1204524109 | bibcode = 2012PNAS..10911178G | doi-access = free }}</ref> GIRK channel blocker (described as "potent"),<ref name="ChungWiddicombe2008">{{cite book | vauthors = Chung KF, Widdicombe J |title=Pharmacology and Therapeutics of Cough |url=https://books.google.com/books?id=Z4kXCSRq0OAC&pg=PA230 |date=30 September 2008 |publisher=Springer Science & Business Media|pages=230– | isbn = 9783540798422 }}</ref><ref name="SoedaFujieda2016">{{cite journal | vauthors = Soeda F, Fujieda Y, Kinoshita M, Shirasaki T, Takahama K | title = Centrally acting non-narcotic antitussives prevent hyperactivity in mice: Involvement of GIRK channels | journal = Pharmacology, Biochemistry, and Behavior | volume = 144 | pages = 26–32 | date = May 2016 | pmid = 26892760 | doi = 10.1016/j.pbb.2016.02.006 |isbn=978-3-540-79842-2 | s2cid = 30118634 | oclc = 612742272 }}</ref><ref name="Yamamoto_2011">{{cite journal | vauthors = Yamamoto G, Soeda F, Shirasaki T, Takahama K | title = [Is the GIRK channel a possible target in the development of a novel therapeutic drug of urinary disturbance?] | journal = Yakugaku Zasshi | volume = 131 | issue = 4 | pages = 523–32 | date = April 2011 | pmid = 21467791 | doi = 10.1248/yakushi.131.523 | doi-access = free }}</ref><ref name="KAWAURAHONDA2010">{{cite journal | vauthors = Kawaura K, Honda S, Soeda F, Shirasaki T, Takahama K | title = [Novel antidepressant-like action of drugs possessing GIRK channel blocking action in rats] | journal = Yakugaku Zasshi | volume = 130 | issue = 5 | pages = 699–705 | date = May 2010 | pmid = 20460867 | doi = 10.1248/yakushi.130.699 | doi-access = free }}</ref> antihistamine (K<sub>i</sub> = 3.8 nM for the H<sub>1</sub> receptor),<ref name="CuzzocreaCatania2011" /><ref name="Gregori-PuigjaneSetola2012" /> and anticholinergic.<ref name="CuzzocreaCatania2011" /><ref name="Korolkovas1988">{{cite book| vauthors = Korolkovas A |title=Essentials of Medicinal Chemistry |url= https://books.google.com/books?id=6hxtAAAAMAAJ |date=16 August 1988 |publisher=Wiley |isbn=978-0-471-88356-2 }}</ref> It is thought that the latter two properties contribute to side effects, such as sedation and somnolence, while the former two may be involved in or responsible for the antitussive efficacy of cloperastine.<ref name="Gregori-PuigjaneSetola2012" /><ref name="ChungWiddicombe2008" />
==Synthesis== [[File:Cloperastine synthesis.svg|thumb|center|501px|class=skin-invert-image|Synthesis:<ref>{{cite journal | vauthors = Arnold H, Brock N, Kuhas E, Lorenz D | title = [Effect of antihistaminic substances. I. Chemical constitution and pharmacological effect of the basic benzhydrylethers] | journal = Arzneimittel-Forschung | volume = 4 | issue = 3 | pages = 189–194 | date = March 1954 | pmid = 13159698 }}</ref> Patents:<ref>Anon., {{Cite patent|GB|1179945}} (1970 to Yoshitomi Pharmaceutical).</ref><ref>Anon., {{Cite patent|GB|670622}} (1952 to Parke Davis & Co).</ref> Isomers:<ref>Laura Puricelli, {{Cite patent|EP|0894794}} (1999 to AESCULAPIUS FARMACEUTICI S.r.l.).</ref> China:<ref>陶文潘, 潘文驰, 潘兴长, 罗泳萍, 樊希祥, {{Cite patent|CN|104327014A}} (2015 to 重庆市恒安化工有限公司).</ref>]]
The halogenation of 4-Chlorobenzhydrol [119-56-2] ('''1''') with phosphorus tribromide in tetrachloromethane gives 1-(Bromophenylmethyl)-4-chlorobenzene [948-54-9] ('''2'''). Treatment with ethylenechlorohydrin (2-Chloroethanol) [107-07-3] ('''3''') gives 1-(4-Chlorobenzhydryl)oxy-2-chloroethane [5321-46-0] ('''4'''). Reaction with piperidine ('''5''') completes the synthesis of ''Cloperastine'' ('''6''').
== See also == * Cough syrup * Noscapine * Codeine; Pholcodine * Dextromethorphan; Dimemorfan * Racemorphan; Dextrorphan; Levorphanol * Butamirate * Pentoxyverine * Tipepidine * Levocloperastine
== References == {{Reflist|2}}
{{Cough and cold preparations}} {{Navboxes | title = Pharmacodynamics | titlestyle = background:#ccccff | list1 = {{Histamine receptor modulators}} {{Ion channel modulators}} {{Muscarinic acetylcholine receptor modulators}} {{Sigma receptor modulators}} }}
Category:1-Piperidinyl compounds Category:4-Chlorophenyl compounds Category:Antitussives Category:Ethanolamines Category:Ethers Category:H1 receptor antagonists Category:M1 receptor antagonists Category:M2 receptor antagonists Category:M3 receptor antagonists Category:M4 receptor antagonists Category:M5 receptor antagonists Category:Potassium channel blockers Category:Sigma receptor modulators