LY-2459989

LY-2459989
Clinical data
Routes of
administration		Oral, intravenous
ATC code
  • None
Pharmacokinetic data
Elimination half-life15 minutes (in rhesus monkeys)[1]
Identifiers
IUPAC name
  • 3-Fluoro-4-[4-{{#parsoidfragment:2}}(2S)-2-pyridin-3-ylpyrrolidin-1-yl]methyl]phenoxy]benzamide
CAS Number
PubChem CID
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC23H22FN3O2
Molar mass391.446 g·mol−1
3D model (JSmol)
SMILES
  • NC(=O)c1ccc(Oc2ccc(CN3CCC[C@H]3c4cccnc4)cc2)c(F)c1
InChI
  • InChI=1S/C23H22FN3O2/c24-20-13-17(23(25)28)7-10-22(20)29-19-8-5-16(6-9-19)15-27-12-2-4-21(27)18-3-1-11-26-14-18/h1,3,5-11,13-14,21H,2,4,12,15H2,(H2,25,28)/t21-/m0/s1
  • Key:DRGHCUTTXWIERB-NRFANRHFSA-N

LY-2459989 is a silent antagonist of the κ-opioid receptor (KOR) that has been developed by Eli Lilly as a radiotracer of that receptor, labeled either with carbon-11[1] or fluorine-18.[2]

Pharmacology

Pharmacokinetics

LY-2795050, CAS# 1346133-08-1 [3]

LY-2459989 exhibits greatly improved central nervous system permeation relative to LY-2795050, with brain levels approximately six times higher than those of its predecessor.[1] The compound has a short duration of action, with only 25% of the compound remaining in serum 30 minutes post-injection in rhesus monkeys, making it an ideal agent for application in biomedical imaging, such as positron emission tomography (PET).[1]

Pharmacodynamics

LY-2459989 possesses high affinity for the KOR (Ki = 0.18 nM) and is highly selective for it over the μ-opioid receptor (Ki = 7.68 nM) and the δ-opioid receptor (Ki = 91.3 nM), showing over 43-fold selectivity for the KOR relative to the other opioid receptors.[1] LY-2459989 is a fluorine-containing analogue and follow-up compound of LY-2795050, the first KOR-selective antagonist radiotracer.[1] Relative to LY-2795050, LY-2459989 displays 4-fold higher affinity for the KOR and similar selectivity.[1]

Earlier analogues of LY-2459989 besides LY-2795050 with similar actions and potential uses have also been described.[4] Short-acting κ antagonists of this type have been shown to produce antidepressant-like effects in animal studies.[5]

See also

References

  1. 1 2 3 4 5 6 7 Zheng MQ, Kim SJ, Holden D, Lin SF, Need A, Rash K, et al. (July 2014). "An Improved Antagonist Radiotracer for the κ-Opioid Receptor: Synthesis and Characterization of (11)C-LY2459989". Journal of Nuclear Medicine. 55 (7): 1185–1191. doi:10.2967/jnumed.114.138701. PMC 4826283. PMID 24854795.
  2. ↑ Cai Z, Li S, Pracitto R, Navarro A, Shirali A, Ropchan J, et al. (January 2017). "Fluorine-18-Labeled Antagonist for PET Imaging of Kappa Opioid Receptors". ACS Chemical Neuroscience. 8 (1): 12–16. doi:10.1021/acschemneuro.6b00268. PMID 27741398.
  3. ↑ "LY-2795050". PubChem. U.S. National Library of Medicine.
  4. ↑ Mitch CH, Quimby SJ, Diaz N, Pedregal C, de la Torre MG, Jimenez A, et al. (December 2011). "Discovery of aminobenzyloxyarylamides as κ opioid receptor selective antagonists: application to preclinical development of a κ opioid receptor antagonist receptor occupancy tracer". Journal of Medicinal Chemistry. 54 (23): 8000–8012. doi:10.1021/jm200789r. PMID 21958337.
  5. ↑ Baynard C, Prisinzano TE, Butelman ER (2021). "Rapid-Onset Anti-Stress Effects of a Kappa-Opioid Receptor Antagonist, LY2795050, Against Immobility in an Open Space Swim Paradigm in Male and Female Mice". Frontiers in Pharmacology. 12 775317. doi:10.3389/fphar.2021.775317. PMC 8645979. PMID 34880762.
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