Chemistry:LY-2459989
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-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
- κ-Opioid receptor § Antagonists
- List of investigational antidepressants
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "An Improved Antagonist Radiotracer for the κ-Opioid Receptor: Synthesis and Characterization of (11)C-LY2459989". Journal of Nuclear Medicine 55 (7): 1185–1191. July 2014. doi:10.2967/jnumed.114.138701. PMID 24854795.
- ↑ "Fluorine-18-Labeled Antagonist for PET Imaging of Kappa Opioid Receptors". ACS Chemical Neuroscience 8 (1): 12–16. January 2017. doi:10.1021/acschemneuro.6b00268. PMID 27741398.
- ↑ "LY-2795050". PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/56851583.
- ↑ "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. December 2011. doi:10.1021/jm200789r. PMID 21958337.
- ↑ "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. 2021. doi:10.3389/fphar.2021.775317. PMID 34880762.
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