Cyprenorphine

Cyprenorphine (M285), N-cyclo-propylmethyl-6,14-endoetheno-7α-(1-hydroxy-1-methylethyl)-6,7,8,14-tetrahydronororipavine, is an opioid drug. It is related to more well-known opioids such as buprenorphine, which is used as an analgesic and for the treatment of opioid addiction, and diprenorphine, which is used as an antidote to reverse the effects of other opioids. It is roughly 35 times as strong as nalorphine.[1]

Cyprenorphine
Clinical data
ATC code
  • none
Legal status
Legal status
  • US: Schedule I
Identifiers
IUPAC name
  • 6,7,8,14-tetrahydro- N-(Cyclopropylmethyl)- 7α-(1-hydroxy-1-methylethyl)- 6,14-endo-ethenonororipavine
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC26H33NO4
Molar mass423.553 g·mol−1
3D model (JSmol)
SMILES
  • CC(C)(O)[C@H]7C[C@]53/C=C/[C@]7(OC)[C@@H]1Oc6c2c(C[C@H]5N(CC[C@@]123)CC4CC4)ccc6O
InChI
  • InChI=1S/C26H33NO4/c1-23(2,29)18-13-24-8-9-26(18,30-3)22-25(24)10-11-27(14-15-4-5-15)19(24)12-16-6-7-17(28)21(31-22)20(16)25/h6-9,15,18-19,22,28-29H,4-5,10-14H2,1-3H3/t18-,19-,22-,24-,25+,26-/m1/s1 Y
  • Key:VSKIOMHXEUHYSI-KNLIIKEYSA-N Y
  (verify)

Cyprenorphine is a powerful antagonist of opioid receptors[2] and a highly potent specific antagonist.[3] It blocks the binding of morphine and etorphine to these receptors.[3]

Cyprenorphine has mixed agonist–antagonist effects at opioid receptors, like those of buprenorphine. However the effects of cyprenorphine are somewhat different, as it produces pronounced dysphoric and hallucinogenic effects which limit its potential use as an analgesic.[4][5]

Cyprenorphine also has been shown to suppress the intake of sweet solution[2] but doesn't suppress the increase in food consumption that is produced by the alpha-2-adrenoceptor antagonist idazoxan. Idazoxan may lead to the release of endogenous opioid peptides and increase food intake, this effect is attenuated by (-)-naloxone but not by the mu/delta-antagonist cyprenorphine.[6]

Medical uses

Cyprenorphine increases locomotor activity.[7] It is normally used to reverse the clinically immobilizing effects of etorphine. These effects are reversed rapidly and almost entirely. Etorphine is a chemical relative of morphine, with similar analgesic characteristics but fewer side effects. For instance, in order to handle polar bears and other large animals, they are immobilized using etorphine and the effects of etorphine reversed as soon as handling is complete using cyprenorphine.[8] Etorphine and cyprenorphine come as white powders in a package and cannot be purchased separately. Both are administered by injection after dissolving in saline.[1] Because etorphine is used to immobilize large, still moving, animals, it is often administered intramuscularly using a dart whereas cyprenorphine can be administered intravenously in the femoral vein of the immobile animal.[8] Unlike other antagonists, used to reverse the effects of etorphine, the dose of cyprenorphine administered depends on the initial dose of etorphine instead of the weight of the animal. The recommended dose of cyprenorphine is three times that of the initial etrophine administered. Although the effects of cyprenorphine typically take from 40 to 60 seconds to kick in, it has been observed to take up to 3 hours in white rhinoceroses.[3]

Adverse effects

Cyprenorphine induces depression over an hour in rats.[7] It has also been found to induce psychotomimetic actions in humans[9] and dysphoria when used as a post-operative analgesic in patients.[10] Because of these side effects, it is seldom used in humans, with diprenorphine preferred instead.

Mechanism of action

Although it is still unclear how cyprenorphine antagonizes the effects of etorphine, it has been suggested that its greater potency may enable it to displace etorphine in mutual binding sites in the brain.[11] 16-methyl Cyprenorphine, an isoform of Cyprenorphine is an antagonist of the delta, mu and kappa opioid receptors. Its elimination rate constants (Ke) at these receptors are 0.68, 0.076 and 0.79 nM respectively.[12]

References
  1. Dobbs, HE (April 1968). "Effect of cyprenorphine (M285), a morphine antagonist, on the distribution and excretion of etorphine (M99), a potent morphine-like drug". The Journal of Pharmacology and Experimental Therapeutics. 160 (2): 407–14. PMID 5647307.
  2. Calcagnetti, DJ; Calcagnetti, RL; Fanselow, MS (January 1990). "Centrally administered opioid antagonists, nor-binaltorphimine, 16-methyl cyprenorphine and MR2266, suppress intake of a sweet solution". Pharmacology, Biochemistry, and Behavior. 35 (1): 69–73. doi:10.1016/0091-3057(90)90206-w. PMID 2315372. S2CID 12321010.
  3. Keep, M. E. "Etorphine hydrochloride antagonists used in the capture of the white rhinoceros Ceratotherium simum simum" (PDF). {{cite journal}}: Cite journal requires |journal= (help)
  4. Bentley KW, Boura AL, Fitzgerald AE, Hardy DG, Mccoubrey A, Aikman ML, Lister RE (April 1965). "Compounds possessing Morphine-antagonizing or Powerful Analgesic Properties". Nature. 206 (4979): 102–3. Bibcode:1965Natur.206..102B. doi:10.1038/206102a0. PMID 14334338. S2CID 4296776.
  5. Lowe G, Williams DI (December 1969). "Some effects of a hallucinogenic compound (cyprenorphine hydrochloride; M 285) on the light reinforced behaviour of rats". Nature. 224 (5225): 1226. Bibcode:1969Natur.224.1226L. doi:10.1038/2241226a0. PMID 5390897. S2CID 4178326.
  6. Jackson HC, Griffin IJ, Nutt DJ (August 1992). "Endogenous opioids may be involved in idazoxan-induced food intake". Neuropharmacology. 31 (8): 771–6. doi:10.1016/0028-3908(92)90040-V. PMID 1356252. S2CID 19966867.
  7. Wray, SR; Cowan, A (1971). "The behavioural effects of levallorphan, cyprenorphine (M285) and amphetamine on repeated Y-maze performance in rats". Psychopharmacologia. 21 (3): 257–67. doi:10.1007/BF00403864. PMID 5095415. S2CID 41484660.
  8. Miller, Robert L.; Will, Gary B. (1976). "Use of M99 Etorphine and Antagonists to Immobilize and Handle Black Bears" (PDF). Bears: Their Biology and Management. 3: 225–234. doi:10.2307/3872770. JSTOR 3872770.
  9. Lowe, G; Williams, DI (1972). "The effect of LSD-25 on light-reinforced behaviour in the rat". Psychopharmacologia. 27 (3): 255–63. doi:10.1007/BF00422806. PMID 4642465. S2CID 31456032.
  10. "J. Lewis, Nathan B. Eddy Award lecture, "In Pursuit of the Holy Grail"" (PDF). Archived from the original (PDF) on 2010-06-17. {{cite journal}}: Cite journal requires |journal= (help)
  11. Cerletti, C; Manara, L; Mennini, T (November 1974). "Proceedings: Brain levels of the potent analgesic etorphine in rats and their functional significance". British Journal of Pharmacology. 52 (3): 440P–441P. PMC 1776995. PMID 4156490.
  12. Smith, C. F. (1987). "16-Me cyprenorphine (RX 8008M): A potent opioid antagonist with some delta selectivity". Life Sciences. 40 (3): 267–74. doi:10.1016/0024-3205(87)90342-0. PMID 3025546.
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