Selective δ opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. ADL5859 is a potent, selective, and orally bioavailable δ opioid receptor agonist.
In vitro: ADL5859 displayed subnanomolar binding affinity at the δ opioid receptor, potent δ agonist activity, and excellent opioid receptor selectivity. Moreover, ADL5859 showed weak inhibitory activity at the hERG channel (78 μM) [1].
In vivo: On the basis of its favorable profile in vitro, ADL5859 was tested in the rat Freund's complete adjuvant (FCA) mechanical hyperalgesia assay. At the screening dose of 3 mg/kg po, ADL5859 produced 100% reversal of hyperalgesia in the inflamed paw. The oral ED50 of ADL5859 in the FCA mechanical hyperalgesia assay was 1.4 mg/kg. The antihyperalgesia produced by ADL5859 (3 mg/kg, po) was reversed by pretreatment with the δ opioid antagonist naltrindole (0.3 mg/kg sc), thus demonstrating a δ receptor mediated effect. Therefore, ADL5859 was selected as a clinical candidate for the treatment of pain [1].
Clinical trial: A clinical study has been conducted to investigate the efficacy and safety of ADL5859 and ADL5747 in participants with pain due to osteoarthritis of the knee, which was supposed to be finished in the middle of 2015.
Reference:
[1] Le Bourdonnec B, Windh RT, Ajello CW, Leister LK, Gu M, Chu GH, Tuthill PA, Barker WM, Koblish M, Wiant DD, Graczyk TM, Belanger S, Cassel JA, Feschenko MS, Brogdon BL, Smith SA, Christ DD, Derelanko MJ, Kutz S, Little PJ, DeHaven RN, DeHaven-Hudkins DL, Dolle RE. 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). J Med Chem. 2008;51(19):5893-6.