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List of orphine opioids

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Orphines is a recently coined term for 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. 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. Subsequently a second group of compounds has also been referred to under this grouping, namely spiropiperidine derivatives typified by spirochlorphine (R6890)[1] where the 4-position of the piperidine ring is fused to an N-phenyl imidazole ring through a shared carbon atom. These are structurally distinct but show a similar overlay in terms of their 3 dimensional shape, and have similar pharmacology and structure-activity relationships. 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.[2][3][4][5][6][7] 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was previously sold as a potent, orally acting analgesic in some European countries under the brand name Burgodin, but withdrawn from sale due to a high potential for overdose.[8] More recent research has focused on the development of compounds such as J-113,397 and Ro65-6570 which have little affinity for the mu opioid receptor and instead act as ligands for the non-psychoactive nociceptin receptor.

Table of Orphines

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Structure Name Chemical name PubChem CAS #
Brorphine 3-{1-[1-(4-bromophenyl)ethyl]piperidin-4-yl}-1H-benzimidazol-2-one 145975294 2244737-98-0
Chlorphine (R5682) 1-{1-[1-(4-chlorophenyl)ethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one 60561198 6440-26-2
Fluorphine 1-{1-[1-(4-fluorophenyl)ethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one 145964378 6440-42-2
Iodorphine 1-{1-[1-(4-iodophenyl)ethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one 165362482
Orphine 1-{1-[1-phenylethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one 21262767 59708-49-5
R4782 3-(1-benzylpiperidin-4-yl)-1H-benzimidazol-2-one 416359 16148-06-4
R6555 [9] 3-[1-[1-(4-chlorophenyl)propyl]piperidin-4-yl]-1H-benzimidazol-2-one 145965998 6440-25-1
Cychlorphine 3-[3-[1-[1-(4-chlorophenyl)ethyl]piperidin-4-yl]-2-oxobenzimidazol-1-yl]propanenitrile 201662 16145-71-4
Cymethorphine 3-[3-[1-[1-(4-methylphenyl)ethyl]piperidin-4-yl]-2-oxobenzimidazol-1-yl]propanenitrile
R5480 1-[1-(3,3-diphenylpropyl)piperidin-4-yl]-1,3-dihydro-2H-1,3-benzimidazol-2-one
Bezitramide 4-[4-(2-oxo-3-propanoyl-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-2,2-diphenylbutanenitrile 61791 15301-48-1
Despropionylbezitramide 4-[4-(2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]-2,2-diphenylbutanenitrile 3086173 83898-28-6
R4837 3-[1-(4-oxo-3,3-diphenylhexyl)piperidin-4-yl]-1H-benzimidazol-2-one 98813 59708-47-3
Cyetodezitramide 3-[2-oxo-3-[1-(4-oxo-3,3-diphenylhexyl)piperidin-4-yl]benzimidazol-1-yl]propanenitrile 24834847 97656-45-6
SR-17018 5,6-dichloro-3-[1-[(4-chlorophenyl)methyl]piperidin-4-yl]-1H-benzimidazol-2-one 130431397 2134602-45-0
J-113,397 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-2H-benzimidazol-2-one 5311194 256640-45-6
Spirorphine [10] 8-(1-phenylethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 44438920 2940-58-1
N-Methyl-spirorphine 8-(1-phenylethyl)-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one
Spirofluorphine 8-[1-(4-fluorophenyl)ethyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one
Spirochlorphine (R6890) 8-[1-(4-chlorophenyl)ethyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 14783734 3222-88-6
Spirobrorphine 8-[1-(4-bromophenyl)ethyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one
R6372 [11] 8-[1-(4-methylphenyl)ethyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 200932 2940-60-5
R5573 8-(3,3-diphenylpropyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 9802509
R5260 8-(4-oxo-3,3-diphenylhexyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 3081947 1109-69-9
Spiroxatrine 8-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 5268 1054-88-2
Ro65-6570 8-(1,2-dihydroacenaphthylen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 10022859 228246-56-8
Ro64-6198 8-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 9844019 280783-56-4

See also

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References

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  1. ^ Stahl KD, van Bever W, Janssen P, Simon EJ (December 1977). "Receptor affinity and pharmacological potency of a series of narcotic analgesic, anti-diarrheal and neuroleptic drugs". European Journal of Pharmacology. 46 (3): 199–205. doi:10.1016/0014-2999(77)90334-x. PMID 22440.
  2. ^ 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.
  3. ^ 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. doi:10.1016/0014-2999(77)90025-5
  4. ^ Emerging analogues of brorphine. UNODC Early Warning Advisory on New Psychoactive Substances (EWA), 6 May 2025
  5. ^ "European Drug Report 2025 – Full Book" (PDF). European Union Drugs Agency (euda.europa.eu). 6 June 2025.
  6. ^ Vandeputte 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. doi:10.1016/j.neuropharm.2024.110113 PMID 39154855
  7. ^ 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. doi:10.1016/j.etdah.2023.100073
  8. ^ 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. PMID 6633692
  9. ^ Kennedy 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. doi:10.1021/acs.jmedchem.8b01136 PMID 30199635
  10. ^ Caldwell 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. doi:10.1016/j.bmcl.2007.01.069 PMID 17289383
  11. ^ Humblet 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. doi:10.1107/S0567740878012388
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