Bucinnazine

{{Short description|Opioid analgesic drug}} {{cs1 config|name-list-style=vanc}} {{Infobox drug | verifiedrevid = | class = Opioid | IUPAC_name = 1-[4-[(''E'')-3-Phenylprop-2-enyl]piperazin-1-yl]butan-1-one | image = AP-237.svg | image_class = skin-invert-image  | tradename = | pregnancy_AU =  | pregnancy_US =  | pregnancy_category = | legal_AU =  | legal_CA = | legal_UK = PSA | legal_US = Schedule I | legal_status = | routes_of_administration =  | bioavailability = | protein_bound = | excretion =  | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 17719-89-0 | CAS_supplemental = <br>17730-82-4 (HCl) | ATC_prefix = | ATC_suffix = | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | PubChem = 6005081 | ChemSpiderID = 4777510 | UNII = J735KL8O54 | synonyms = AP-237  | C = 17 | H = 24 | N = 2 | O = 1 | smiles = CCCC(=O)N1CCN(CC1)C/C=C/C2=CC=CC=C2 | StdInChI = 1S/C17H24N2O/c1-2-7-17(20)19-14-12-18(13-15-19)11-6-10-16-8-4-3-5-9-16/h3-6,8-10H,2,7,11-15H2,1H3/b10-6+ | StdInChIKey = ZQBMUHABRSEAIK-UXBLZVDNSA-N }}

'''Bucinnazine''' ('''AP-237''', '''1-butyryl-4-cinnamylpiperazine''') is an opioid analgesic drug that was widely used in China to treat pain in cancer patients as of 1986.<ref name="Qing1986">{{cite journal |vauthors=Qing T, Zhi-Ji C, Wei-Ping W | title = Experimental Study on the Dependence-Producing Properties of Qiang Tong Ding (AP-237) | journal = Chin. J. Clin. Pharmacol. | date = 1986 | issue = 2 | url = http://en.cnki.com.cn/Article_en/CJFDTotal-GLYZ198602003.htm}}</ref> It is one of the most potent compounds among a series of piperazine-amides first synthesized and reported in Japan in the 1970s.<ref>{{cite journal | vauthors = Nishimura N, Kiuchi M, Kanetake Y, Takahashi T | title = [Clinical exaluation of a new analgesic agent Ap-237] | journal = Masui. The Japanese Journal of Anesthesiology | volume = 19 | issue = 6 | pages = 653–656 | date = June 1970 | pmid = 4916908 }}</ref><ref>{{cite journal | vauthors = Carrano RA, Kimura KK, McCurdy DH | title = Analgesic and tolerance studies with AP-237, a new analgesic | journal = Archives Internationales de Pharmacodynamie et de Therapie | volume = 213 | issue = 1 | pages = 41–57 | date = January 1975 | pmid = 1156018 }}</ref><ref>{{cite journal | vauthors = Carrano RA, Kimura KK, Landes RC, McCurdy DH | title = General pharmacology of a new analgesic-AP-237 | journal = Archives Internationales de Pharmacodynamie et de Therapie | volume = 213 | issue = 1 | pages = 28–40 | date = January 1975 | pmid = 1156016 }}</ref> Bucinnazine has analgesic potency comparable to that of morphine, but with a relatively higher therapeutic index.

The drug was initially claimed to be a non-narcotic analgesic. However, subsequent studies have shown bucinnazine and similar acyl piperazines to be potent and selective agonists of μ-opioid receptor (MOR) with relatively low affinity for the δ-opioid receptor and the κ-opioid receptor.<ref>{{cite journal | vauthors = Barlocco D, Cignarella G, Greco G, Novellino E | title = Computer-aided structure-affinity relationships in a set of piperazine and 3,8-diazabicyclo[3.2.1]octane derivatives binding to the mu-opioid receptor | journal = Journal of Computer-Aided Molecular Design | volume = 7 | issue = 5 | pages = 557–571 | date = October 1993 | pmid = 8294946 | doi = 10.1007/bf00124362 | s2cid = 23360530 | bibcode = 1993JCAMD...7..557B }}</ref> In accordance with these studies, results from the intravenous self-administration experiments in rats showed that bucinnazine has a marked reinforcing effect with tolerance and dependence quickly developing.<ref name="Qing1986" /> In addition, the opioid receptor antagonist naloxone reverses the effect of bucinnazine and precipitates withdrawal symptoms in bucinnazine treated rats further indicating a mechanism of analgesia mediated via selective agonist activity at μ-opioid receptors.

==Derivatives== 2-Methyl-AP-237 has been sold on the grey market as a designer opioid, first identified by a police forensic laboratory in Slovenia in March 2019.<ref>{{cite web | url = https://www.policija.si/apps/nfl_response_web/0_Analytical_Reports_final/2-Methyl-AP-237-ID-2053-19_report.pdf | title = Analytical Report 2-Methyl-AP-237 | date = 19 March 2019 | location = Ljubljana, Slovenia | publisher = National Forensic Laboratory }}</ref><ref>{{cite journal | vauthors = Fogarty MF, Vandeputte MM, Krotulski AJ, Papsun D, Walton SE, Stove CP, Logan BK | title = Toxicological and pharmacological characterization of novel cinnamylpiperazine synthetic opioids in humans and in vitro including 2-methyl AP-237 and AP-238 | journal = Archives of Toxicology | volume = 96 | issue = 6 | pages = 1701–1710 | date = June 2022 | pmid = 35275255 | doi = 10.1007/s00204-022-03257-7 | bibcode = 2022ArTox..96.1701F | s2cid = 247383361 | url = https://biblio.ugent.be/publication/8751262/file/01GSZ6CH6J9EAPZJNW2DX22KJT | url-access = subscription }}</ref><ref>{{cite journal | vauthors = Giorgetti A, Brunetti P, Pelotti S, Auwärter V | title = Detection of AP-237 and synthetic cannabinoids on an infused letter sent to a German prisoner | journal = Drug Testing and Analysis | volume = 14 | issue = 10 | pages = 1779–1784 | date = October 2022 | pmid = 35918775 | pmc = 9804899 | doi = 10.1002/dta.3351 | doi-access = free }}</ref> In 2023, the United States Department of Justice took criminal action against two individuals for selling 2-Methyl-AP-237 under the false pretenses that such product was intended for 'research purposes' only. One of the pair was sentenced to five years in federal prison.<ref>{{Cite journal |last=Affairs |first=Office of Regulatory |date=2023-10-30 |title=New Braunfels Man Sentenced to Five Years in Prison for Selling Misbranded Drugs |url=https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/press-releases/new-braunfels-man-sentenced-five-years-prison-selling-misbranded-drugs |archive-url=https://web.archive.org/web/20231108212721/https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/press-releases/new-braunfels-man-sentenced-five-years-prison-selling-misbranded-drugs |url-status=dead |archive-date=November 8, 2023 |journal=DOJ |language=en}}</ref>

The WHO and the Ministry of Social Affairs, Health, Care and Consumer Protection have published reports on 2-Methyl-AP-237. According to their analysis, it is a little bit less potent than fentanyl and can be reversed using naltrexone. There haven't been any studies on its systemic toxicity but there have been overdose deaths linked to it, most in combination with other drugs. It is primarily consumed orally or through snorting. While the methyl substitution creates a stereocenter, the drug is sold as the racemate.<ref>{{cite web | title=Sachverständigengutachten zur Festlegung der Grenzmenge gemäß Paragraph 28b Suchtmittelgesetz für 2-Methyl AP-237 | url=https://www.sozialministerium.gv.at/dam/jcr:20742320-483b-4725-a1ec-3d84b650e8bb/2-methyl-ap-237_2023-10-29.pdf | access-date=2025-11-19}}</ref><ref>{{cite web | title=Critical review report: 2-Methyl AP-237 | url=https://cdn.who.int/media/docs/default-source/controlled-substances/45th-ecdd/2-methyl-ap-237_draft.pdf?sfvrsn=768c7c03_1 | access-date=2025-11-19}}</ref>

==See also== * AP-238 * Azaprocin * Diphenpipenol * MT-45 * Sunifiram

==References== {{reflist}}

Category:Analgesics Category:Euphoriants Category:Mu-opioid receptor agonists Category:Synthetic opioids Category:Piperazines Category:Amides Category:Designer drugs