ADL5859 Hydrochloride is a novel δ-opioid agonists that shows good oral bioavailability and analgesic and antidepressive effects in the rat and represent potential drugs for chronic pain treatment. ADL5859 HCl significantly reduced inflammatory and neuropathic pain. The antiallodynic effects of ADL5859 was abolished in constitutive δ-receptor KO mice and strongly diminished in δ-receptor cKO mice. ADL5859 Hydrochloride did not induce either hyperlocomotion or receptor internalization in vivo. ADL5859 also displayed weak inhibitory activity at the hERG channel (IC50 = 78 µM). ADL5859 HCl efficiently reduces inflammatory and neuropathic pain mainly by recruiting δ-opioid receptors expressed by peripheral Nav1.8-expressing neurons.
|Cell lines||CHO cells expressing the human delta opioid receptor|
|Preparation method||Receptor-Mediated [35S]GTPγS Binding.Receptor-mediated [35S]GTPγS binding was performed by modifications of the methods of Selley and collaborators3 and Traynor and Nahorski.4 Assays were carried out in 96-well FlashPlates (Perkin-Elmer Life Sciences, Inc, Boston, MA). Membranes prepared from CHO cells expressing the human delta opioid receptor (50-100 μg of protein) were added to assay mixtures containing agonist, approximately 100 000 dpm (100 pM) [35S]GTPγS, 3.0 μM GDP, 75 mM NaCl, 15 mM MgCl22, 1.0 mM EGTA, 1.1 mM dithiothreitol, 10 mg/L leupeptin, 10 mg/L pepstatin A, 200 mg/L bacitracin, and 0.5 mg/L aprotinin in 50 mM Tris-HCl buffer, pH 7.8. After incubation at room temperature for 1 h, the plates were sealed and centrifuged at 800 x g in a swinging bucket rotor for 5 min and bound radioactivity was determined with a TopCount microplate scintillation counter (Packard Instrument Co., Meriden, CT). Agonist potencies were assessed by measuring stimulation of [35S]GTPγS binding by a series of concentrations of agonist, using BW373U86 as a reference agonist. The concentration to give half-maximal stimulation (EC50) was determined by nonlinear regression using Prism.|
|Concentrations||0~10 n M|
|Incubation time||60 min|
|Animal models||Inflammatory Pain and Neuropathic Pain Mouse Models and δ-Opioid Receptor Knockout Mice|
|Formulation||distilled water with 0.5% hydroxypropyl methylcellulose/ 0.1% Tween 80|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 80 mg/mL|
δ-Opioid mechanisms for ADL5747 and ADL5859 effects in mice: analgesia, locomotion, and receptor internalization.
Nozaki C, et al. J Pharmacol Exp Ther. 2012 Sep;342(3):799-807. PMID: 22700431.
Potent, orally bioavailable delta opioid receptor agonists for the treatment of pain: discovery of N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4'-piperidine]-4-yl)benzamide (ADL5859).
Le Bourdonnec B, et al. J Med Chem. 2008 Oct 9;51(19):5893-6. PMID: 18788723.
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