Orphine is a class of synthetic opioid analgesic drugs, first developed in the 1960s and 1970s by Paul Janssen but categorised as their own distinct grouping by international drug control agencies, such as the EUDA and UNODC in 2025. These have emerged as designer drugs in recent years following increasing legislative controls on earlier families of synthetic opioids such as fentanyls and nitazenes.NOVEL PSYCHOACTIVE SUBSTANCES: ORPHINES – BRORPHINE, CYCHLORPHINE, AND BEYOND. Legislative Analysis and Public Policy Association April 2026Marchei E, Graziano S, Pichini S, Farré M. Brorphine and Its Analogues: Pharmacology, Toxicology, and Biomonitoring. Ther Drug Monit. 2026 Aug 1;48(4):424-431.
Orphines are not structural analogues of morphine (known as morphinans), despite the similar name. Initially, the term referred to compounds such as brorphine and bezitramide (which are related to fentanyls, but with the aniline nitrogen cyclised into a benzimidazole ring system), but subsequently a second group of compounds also came to be referred to under this epithet, namely the spiropiperidine derivatives typified by spirochlorphine (R6890), where the 4-position of the piperidine ring is fused to an N-phenyl imidazole ring through a shared carbon atom. Judged by molecular structure these are distinct types, but they show a similar overlay in terms of their three-dimensional shape, and have similar structure-activity relationships and pharmacology.
As with many other opioid drugs of this type, replacing the "tail" substitution on the piperidine with a p-fluorobutyrophenone produces antipsychotics instead of opioids (benperidol and spiperone respectively). Other substitutions such as N-phenethyl produce a mixture of both opioid and neuroleptic activity which is generally unsuited for either application, so the compounds with potent opioid activity tend to be those with substituted alpha-methyl benzyl or 3,3-diphenylpropyl chains attached to the piperidine nitrogen, as this favors mu opioid receptor binding but disfavors the antagonist binding at dopamine D2-like receptors which produces antipsychotic activity.P. A. J. Janssen and C. A. M. Van der Eycken: The chemical anatomy of potent morphine-like analgesics. In: Drugs Affecting the Central Nervous System, vol. 2, p. 25. Ed. A. Burger. Marcel Dekker, Inc., New York 1968.Leysen J, Tollenaere JP, Koch MHJ, Laduron P. Differentiation of opiate and neuroleptic receptor binding in rat brain. European Journal of Pharmacology 1977; 43(3):253-267. Emerging analogues of brorphine. UNODC Early Warning Advisory on New Psychoactive Substances (EWA), 6 May 2025Vandeputte MM, Bilel S, Tirri M, Corli G, Bassi M, Layle NK, Fantinati A, Walther D, Iula DM, Baumann MH, Stove CP, Marti M. Elucidating the harm potential of brorphine analogues as new synthetic opioids: Synthesis, in vitro, and in vivo characterization. Neuropharmacology. 2024 Dec 1;260:110113. Bilel S, Vandeputte MM, et al. In Vivo Pharmaco-Toxicological Characterization of Brorphine and its Possible Emerging Analogues Orphine, Fluorphine, Chlorphine and Iodorphine. Emerging Trends in Drugs, Addictions, and Health 2024; (4): 100073.
A large number of compounds from these two groups are known, but few have been used for legitimate medical applications, aside from bezitramide which was previously sold as a potent, orally acting analgesic in some European countries under the brand name Burgodin, but withdrawn from sale due to a high potential for overdose.de Vos JC, Rohof OJ, Bernsen PJ, Conemans JM, van Unnik AJ. Dood door één tablet Burgodin (Death caused by one tablet of Burgodin) (Dutch). Ned Tijdschr Geneeskd. 1983 Aug 20;127(34):1552-3.
More recent research has focused on the development of compounds such as J-113,397 and Ro65-6570, which have low affinity for the mu opioid receptor and instead act as ligands for the non-psychoactive nociceptin receptor.
Table of orphines
Structure NameChemical FormulaMolecular Weight (g/mol) Chemical name PubChem CAS #BrorphineC20H22BrN3O 400.33-{1-[1-(4-bromophenyl)ethyl]piperidin-4-yl}-1H-benzimidazol-2-one1459752942244737-98-0Chlorphine (R5682)C20H22ClN3O355.91-{1-[1-(4-chlorophenyl)ethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one605611986440-26-2FluorphineC20H22FN3O339.41-{1-[1-(4-fluorophenyl)ethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one1459643786440-42-2IodorphineC20H22IN3O447.31-{1-[1-(4-iodophenyl)ethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one165362482MethylorphineC21H25N3O335.51-(1-(1-(p-tolyl)ethyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one17296806147434-20-8Methoxyorphine Yurchenko R, Vydra T, Galetskaya I, Юрченко Л, Piatsetskaya A, Павловец Ю. Psychoactive products market observation. Trend analysis. AIPSIN Issue 78. June 2026. C21H25N3O2351.51,3-dihydro-1-[1-[1-(4-methoxyphenyl)ethyl]-4-piperidinyl]-2H-benzimidazol-2-one1459638502244737-99-1OrphineC20H23N3O321.41-{1-[1-phenylethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one2126276759708-49-5R4782C19H21N3O307.23-(1-benzylpiperidin-4-yl)-1H-benzimidazol-2-one41635916148-06-4R6555Kennedy NM, Schmid CL, Ross NC, Lovell KM, Yue Z, Chen YT, Cameron MD, Bohn LM, Bannister TD. Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias. J Med Chem. 2018 Oct 11;61(19):8895-8907. C21H24ClN3O369.23-[1-[1-(4-chlorophenyl)propyl]piperidin-4-yl]-1H-benzimidazol-2-one1459659986440-25-1N-Propionitrile orphine Wood R, Moore R, Iula D. The detection of N-propionitrile orphine in a urine sample. J Anal Toxicol. 2026 May 26;50(5):bkag024. C23H26N4O374.53-[3-[1-(1-phenylethyl)piperidin-4-yl]-2-oxobenzimidazol-1-yl]propanenitrileCychlorphine (N-propionitrile chlorphine)C23H25ClN4O408.93-[3-[1-[1-(4-chlorophenyl)ethyl]piperidin-4-yl]-2-oxobenzimidazol-1-yl]propanenitrile20166216145-71-4N-Propionitrile brorphine (Cybrorphine) Synthetic Opioid, N-Propionitrile Brorphine. Office of Addiction Services and Supports 7 July 2026C23H25BrN4O452.13-[3-[1-[1-(4-bromophenyl)ethyl]piperidin-4-yl]-2-oxobenzimidazol-1-yl]propanenitrileN-Propionitrile 5-chloro desmethylbrorphine DEA Overdose Surveillance Exchange (DOSE), DEA-SFL1-DOSE-26-003, June 2026C22H22BrClN4O473.8 3-(3-(1-(4-bromobenzyl)piperidin-4-yl)-6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)propanenitrileCymethorphine (N-Propionitrile methylorphine, Warorphan)C24H28N4O388.23-[3-[1-[1-(4-methylphenyl)ethyl]piperidin-4-yl]-2-oxobenzimidazol-1-yl]propanenitrile92281-62-4R5480C27H29N3O383.21-[1-(3,3-diphenylpropyl)piperidin-4-yl]-1,3-dihydro-2H-1,3-benzimidazol-2-oneBezitramideC31H32N4O2492.64-[4-(2-oxo-3-propanoyl-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-2,2-diphenylbutanenitrile6179115301-48-1DespropionylbezitramideC28H28N4O436.64-[4-(2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]-2,2-diphenylbutanenitrile308617383898-28-6R4837 (Etodezitramide)C30H33N3O2467.63-[1-(4-oxo-3,3-diphenylhexyl)piperidin-4-yl]-1H-benzimidazol-2-one9881359708-47-3CyetodezitramideC33H36N4O2520.73-[2-oxo-3-[1-(4-oxo-3,3-diphenylhexyl)piperidin-4-yl]benzimidazol-1-yl]propanenitrile2483484797656-45-6 SR-11501 C22H25N3O3 379.5 3-[1-[1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]piperidin-4-yl]-1H-benzimidazol-2-one 146025598 ? SR-14968 C20H20BrCl2N3O 469.2 3-[1-[1-(4-bromophenyl)ethyl]piperidin-4-yl]-5,6-dichloro-1H-benzimidazol-2-one 130431386 2133455-40-8 SR-14969 C20H19Cl3FN3O 442.7 5,6-dichloro-3-[1-[1-(4-chloro-2-fluorophenyl)ethyl]piperidin-4-yl]-1H-benzimidazol-2-one 146025599 ? SR-15098 C19H17Cl3FN3O 428.7 5,6-dichloro-3-[1-[(4-chloro-2-fluorophenyl)methyl]piperidin-4-yl]-1H-benzimidazol-2-one 130431384 ? SR-15099 C19H18BrCl2N3O 455.2 3-[1-[(4-bromophenyl)methyl]piperidin-4-yl]-5,6-dichloro-1H-benzimidazol-2-one 130431412 ?SR-11099C19H19Cl2N3O376.35-chloro-1-[1-[(2-chlorophenyl)methyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one1459787865-Chloro desmethylchlorphineC19H19Cl2N3O376.35-chloro-1-[1-[(4-chlorophenyl)methyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one2575731-77-8 SR-17018 (5,6‑dichloro-desmethyl-chlorphine) C19H18Cl3N3O 410.7 5,6-dichloro-3-[1-[(4-chlorophenyl)methyl]piperidin-4-yl]-1H-benzimidazol-2-one 130431397 2134602-45-0J-113,397C24H37N3O2399.61-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-2H-benzimidazol-2-one5311194256640-45-6SR-14136C22H25N3O347.5 3-[(2R,6S,9aR)-6-phenyl-2,3,4,6,7,8,9,9a-octahydro-1H-quinolizin-2-yl]-1H-benzimidazol-2-one10066285 Muzepan1 C21H22BrCl2N3O 483.2 3-[1-[1-(4-bromophenyl)ethyl]azepan-4-yl]-5,6-dichloro-1H-benzimidazol-2-one 178248567 ? Muzepan2 C21H21Cl3FN3O 456.8 3-[1-[1-(2-fluoro-4-chlorophenyl)ethyl]azepan-4-yl]-5,6-dichloro-1H-benzimidazol-2-one ? ?SpirorphineCaldwell JP, Matasi JJ, Zhang H, Fawzi A, Tulshian DB. Synthesis and structure-activity relationships of N-substituted spiropiperidines as nociceptin receptor ligands. Bioorg Med Chem Lett. 2007 Apr 15;17(8):2281-4. C21H25N3O335.28-(1-phenylethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one444389202940-58-1N-Methyl-spirorphineC22H27N3O349.28-(1-phenylethyl)-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-oneSpirofluorphineC21H24FN3O353.28-[1-(4-fluorophenyl)ethyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-oneSpirochlorphine (R6890)C21H24ClN3O369.28-[1-(4-chlorophenyl)ethyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one147837343222-88-6SpirobrorphineC21H24BrN3O414.38-[1-(4-bromophenyl)ethyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one177864517R6372Humblet C, Burnotte C, Evrard G, Durant F. 8-[1-(4-Methylphenyl)ethyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 0.5 methanol:R6372. Acta Cryst. 1978; B34: 3830-3832. C22H27N3O349.58-[1-(4-methylphenyl)ethyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one2009322940-60-5R5573C28H31N3O425.68-(3,3-diphenylpropyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one9802509R-5260C31H35N3O2481.68-(4-oxo-3,3-diphenylhexyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one30819471109-69-9BRN 0633766Watson B, Hohlweg R, Thomsen C. Novel 1,3,8-triazaspiro[4.5decanones with high affinity for opioid receptor subtypes. WO 1999/059997]Chen Z, Victory S. Triazaspiro compounds useful for treating or preventing pain. US6995168C29H30N4O450.64-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-2,2-diphenylbutanenitrile140011062-15-3SpiroxatrineC22H25N3O3379.58-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one52681054-88-2Ro65-6570C22H25N3O383.58-(1,2-dihydroacenaphthylen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one10022859228246-56-8Ro64-6198C26H31N3O401.58-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one9844019280783-56-4
See also List of benzimidazole opioids List of fentanyl analogues Utopioid (drug class)
References