Potent, Orally Bioavailable Delta Opioid Receptor Agonists for the Treatment of Pain: Discovery of <i>N</i>,<i>N</i>-Diethyl-4-(5-hydroxyspiro[chromene-2,4′-piperidine]-4-yl)benzamide (ADL5859)

Bourdonnec, Bertrand Le; Windh, Rolf T.; Ajello, Christopher W.; Leister, Lara K.; Gu, Minghua; Chu, Guowei; Tuthill, Paul A.; Barker, William M.; Koblish, Michael; Wiant, Daniel D.; Graczyk, Thomas M.; Belanger, Serge; Cassel, Joel; Feschenko, Marina S.; Brogdon, Bernice L.; Smith, Steven A.; Christ, David D.; Derelanko, Michael J.; Kutz, Steve; Little, Patrick; DeHaven, Robert N.; DeHaven‐Hudkins, Diane L.; Dolle, Roland E.

doi:10.1021/jm8008986

Cited by 89 publications

(81 citation statements)

References 21 publications

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“…At the same time, they may also underlie the proconvulsant effects of exogenous DOPr agonists (Broom et Importantly, the potential to generate seizures is not the same for all DOPr agonists. This potential is associated with SNC80 (Broom et al, 2002;Jutkiewicz et al, 2005Jutkiewicz et al, , 2006, BW373U86 (Jutkiewicz et al, 2006), and deltorphin II (De Sarro et al, 1992;Di Giannuario et al, 2001) but not by KNT-127 (Saitoh et al, 2011), ADL5859 (Le Bourdonnec et al, 2008), or ADL5747 (Le Bourdonnec et al, 2009). ADL compounds that were devoid of proconvulsive actions in preclinical models have also been tested for acute (ClinicalTrials.gov identifier NCT00993863) and chronic (ClinicalTrials.…”

Section: D-opioid Receptors and Activation Of G Protein-coupled Inmentioning

confidence: 99%

Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

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Section: D-opioid Receptors and Activation Of G Protein-coupled Inmentioning

confidence: 99%

Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

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“…Control groups for SNC80 received intraperitoneal saline. ADL5747 and ADL5859 (10 -300 mg/ kg, Adolor Corporation, Exton, PA) were dissolved in distilled water with 0.5% hydroxypropyl methylcellulose/0.1% Tween 80 and administered by gavage orally as described previously for rats (Le Bourdonnec et al, 2008) for systemic administration. In a clinical phase I study with ADL5859, this route was well tolerated and suitable for daily dosing.…”

Section: Drugsmentioning

confidence: 99%

“…The novel nonpeptidic compounds N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4Ј-piperidine]-4-yl)benzamide (ADL5859) (Le Bourdonnec et al, 2008) and N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4Ј-piperidine]-4-yl)benzamide (ADL5747) (Le Bourdonnec et al, 2009) were developed with structures distinct from other ␦-agonist classes to obtain molecules with higher selectivity for ␦ receptors (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

“…They showed ␦-opioid selectivity based on nanomolar affinities and signaling potencies for the receptor in vitro, with no detectable binding at more than 100 nonopioid receptors, channels, or enzymes (Le Bourdonnec et al, 2008Bourdonnec et al, , 2009. In rats, the two drugs display good oral bioavailability and produce antidepressant (ADL5859) and antihyperalgesic effects in a model of inflammatory pain (Le Bourdonnec et al, 2008). Here, we took advantage of several existing mutant mouse lines targeting the ␦-opioid receptor gene to investigate the molecular bases of ADL5747 and ADL5859 effects in vivo.…”

Section: Introductionmentioning

confidence: 99%

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δ-Opioid Mechanisms for ADL5747 and ADL5859 Effects in Mice: Analgesia, Locomotion, and Receptor Internalization

Nozaki

Bourdonnec

Reiss

et al. 2012

J Pharmacol Exp Ther

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N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4Ј-piperidine]-4-yl) benzamide (ADL5859) and N,N-diethyl-3-hydroxy-4-(spiro-[chromene-2,4Ј-piperidine]-4-yl)benzamide (ADL5747) are novel ␦-opioid agonists that show good oral bioavailability and analgesic and antidepressive effects in the rat and represent potential drugs for chronic pain treatment. Here, we used genetic approaches to investigate molecular mechanisms underlying their analgesic effects in the mouse. We tested analgesic effects of ADL5859 and ADL5747 in mice by using mechanical sensitivity measures in both complete Freund's adjuvant and sciatic nerve ligation pain models. We examined their analgesic effects in ␦-opioid receptor constitutive knockout (KO) mice and mice with a conditional deletion of ␦-receptor in peripheral voltage-gated sodium channel (Nav)1.8-expressing neurons (cKO mice). Both ADL5859 and ADL5747, and the prototypical ␦ agonist 4-[(R)-[(2S,5R)-4-allyl-2,5-dimethyl-piperazin-1-yl]-(3-methoxyphenyl)methyl]-N,Ndiethyl-benzamide (SNC80) as a control, significantly reduced inflammatory and neuropathic pain. The antiallodynic effects of all three ␦-opioid agonists were abolished in constitutive ␦-receptor KO mice and strongly diminished in ␦-receptor cKO mice. We also measured two other well described effects of ␦ agonists, increase in locomotor activity and agonist-induced receptor internalization by using knock-in mice expressing enhanced green fluorescence protein-tagged ␦ receptors. In contrast to SNC80, ADL5859 and ADL5747 did not induce either hyperlocomotion or receptor internalization in vivo. In conclusion, both ADL5859 and ADL5747 showed efficient pain-reducing properties in the two models of chronic pain. Their effects were mediated by ␦-opioid receptors, with a main contribution of receptors expressed on peripheral Nav1.8-positive neurons. The lack of in vivo receptor internalization and locomotor activation, typically induced by SNC80, suggests agonist-biased activity at the receptor for the two drugs.

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“…To validate the heteromer assay for this purpose, we tested four DOR-selective compounds for their activity on DOR homomers (DOR 333 -G qi4 1 DOR), MOR homomers (MOR 354 -G qi4 1 MOR), and DOR-MOR heteromers (DOR 333 -G qi4 1 MOR; MOR 354 -G qi4 1 DOR). The set included deltorphin II, an amphibian-derived peptide (Kreil et al, 1989); a DOR agonist currently in phase 2 clinical trials, ADL5859 (Le Bourdonnec et al, 2008); as well as two agonists, SNC80 and ARM1000390, that differ in their ability to internalize the DOR (Pradhan et al, 2009). Deltorphin II displayed similar activity on the DOR homomer and the DOR-MOR heteromers ( Fig.…”

Section: Screening For Homomer-and Heteromer-selective Compoundsmentioning

confidence: 99%

Novel Screening Assay for the Selective Detection of G-Protein-Coupled Receptor Heteromer Signaling

Rijn

Harvey

Brissett

et al. 2012

J Pharmacol Exp Ther

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Drugs targeting G-protein-coupled receptors (GPCRs) make up more than 25% of all prescribed medicines. The ability of GPCRs to form heteromers with unique signaling properties suggests an entirely new and unexplored pool of drug targets. However, current in vitro assays are ill equipped to detect heteromer-selective compounds. We have successfully adapted an approach, using fusion proteins of GPCRs and chimeric G proteins, to create an in vitro screening assay (in human embryonic kidney cells) in which only activated heteromers are detectable. Here we show that this assay can demonstrate heteromer-selective G-protein bias as well as measure transinhibition. Using this assay, we reveal that the d-opioid receptor agonist ADL5859, which is currently in clinical trials, has a 10-fold higher potency against d-opioid receptor homomers than d/m-opioid receptor heteromers (pEC 50 5 6.7 6 0.1 versus 5.8 6 0.2). The assay enables the screening of large compound libraries to identify heteromer-selective compounds that could then be used in vivo to determine the functional role of heteromers and develop potential therapeutic agents.

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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)

Cited by 89 publications

References 21 publications

Molecular Pharmacology ofδ-Opioid Receptors

Molecular Pharmacology ofδ-Opioid Receptors

δ-Opioid Mechanisms for ADL5747 and ADL5859 Effects in Mice: Analgesia, Locomotion, and Receptor Internalization

Novel Screening Assay for the Selective Detection of G-Protein-Coupled Receptor Heteromer Signaling

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