The Novel, Orally Active, Delta Opioid RWJ-394674 Is Biotransformed to the Potent Mu Opioid RWJ-413216

Codd, Ellen E.; Carson, John R.; Colburn, Raymond W.; Dax, Scott L.; Desai-Krieger, Daksha; Martinez, Rebecca P.; McKown, Linda A.; Neilson, LouAnn; Pitis, Philip; Stahle, Paul L.; Stone, Dennis J.; Streeter, Anthony J.; Wu, Wu‐Nan; Zhang, Sui‐Po

doi:10.1124/jpet.106.104208

Cited by 14 publications

(12 citation statements)

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“…A close look at our new compounds ( 5–13 ), a similar behaviour might be theoretically expected from all N-methylated analogues ( 5 , 8–11 ). On the basis of this hypothesis,30 we chose a potent and selective δ antagonist ( 10 ) as a potential protodrug of the potent and selective δ agonist 4 . However, preliminary enzymatic degradation studies ( Supporting Information ) failed to demonstrate and support this assumption; in fact, both compounds 4 and 10 appeared to be fully stable to enzymic degradation for 4 h and 2 h in plasma and brain homogenate, respectively.…”

Section: Resultsmentioning

confidence: 99%

Further Studies on Lead Compounds Containing the Opioid Pharmacophore Dmt-Tic

et al. 2008

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Opioids containing the Dmt-Tic pharmacophore, especially the δ agonists H-Dmt-Tic-Gly-NH-Ph 1 and H-Dmt-Tic-NH-(S)CH(CH 2 -COOH)-Bid 4 (UFP-512) were evaluated for the influence of the substitution of Gly with aspartic acid, its chirality, and the importance of the -NH-Ph and N 1 H-Bid hydrogens relative to δ agonism. The results provide the following conclusions: (i) Asp increases δ selectivity by lowering μ affinity; (ii) -NH-Ph and N 1 H-Bid nitrogen methylation transforms δ agonists into δ antagonists; (iii) substitution of Gly with L-Asp/D-Asp in the δ agonist H-Dmt-TicGly-NH-Ph resulted in δ antagonists, while the same substitution in the δ agonist H-Dmt-Tic-NH-CH 2 -Bid yielded more selective δ agonists, H-Dmt-Tic-NH-(S)CH(CH 2 -COOH)-Bid and H-DmtTic-NH-(R)CH(CH 2 -COOH)-Bid; (iv) L-Asp seems important only for functional bioactivity, not receptor affinity; (v) H-Dmt-Tic-NH-(S)CH(CH 2 -COOH)-Bid(N 1 -Me) (10) revealed analgesia similar to 4, which was reversed by naltrindole only in the tail-flick test. Compounds 4 and 10 had opposite behaviours in mice: 4 caused agitation, while 10 gave sedation and convulsions.

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Section: Resultsmentioning

confidence: 99%

Further Studies on Lead Compounds Containing the Opioid Pharmacophore Dmt-Tic

et al. 2008

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“…157 7 RWJ-394674 i Sub-nM affinity for DOR. 158 ii Oral antinociceptive activity. 158 iii Undergoes hepatic metabolism (N-desethyl) to a potent MOR agonist.…”

Section: 146mentioning

confidence: 99%

“…158 ii Oral antinociceptive activity. 158 iii Undergoes hepatic metabolism (N-desethyl) to a potent MOR agonist. 158 8 ALD5747 and ALD5859 i Structurally distinct DOR full agonists with high affinity and selectivity.…”

Section: 146mentioning

confidence: 99%

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Delta opioid agonists: a concise update on potential therapeutic applications

Peppin

Raffa

2015

J Clin Pharm Ther

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SUMMARYWhat is known and objective: The endogenous opioid system co-evolved with chemical defences, or at times symbiotic relationships, between plants and other autotrophs and heterotrophic predators -thus, it is not surprising that endogenous opioid ligands and exogenous mimetic ligands produce diverse physiological effects. Among the endogenous opioid peptides (endomorphins, enkephalins, dynorphins and nociception/orphanin FQ) derived from the precursors encoded by four genes (PNOC, PENK, PDYN and POMC) are the pentapeptides Met-enkephalin (Tyr-Gly-Gly-Phe-Met) and Leu-enkephalin (Tyr-Gly-Gly-PheLeu). The physiological effects of the enkephalins are mediated via 7-transmembrane G protein-coupled receptors, including delta opioid receptor (DOR). We present a concise update on the status of progress and opportunities of this approach. Methods: A literature search of the PUBMED database and a combination of keywords including delta opioid receptor, analgesia, mood and individual compounds identified therein, from industry and other source, and from www.clinicaltrials.com. Results and discussion: DOR agonist and antagonist ligands have been developed with ever increasing affinity and selectivity for DOR over other opioid receptor subtypes and studied for therapeutic utility, primarily for pain relief, but also for other clinical endpoints. What is new and conclusion: Selective DOR agonists have been designed with a large increase in therapeutic window for a variety of potential CNS applications including pain, depression, and learning and memory among others. WHAT IS KNOWN AND OBJECTIVE

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“…These assays were performed essentially as described previously (Codd et al, 2006). Membranes from endogenously DOR expressing NG-108 cells or recombinant -opioid receptor expressing Chinese hamster ovary cells (CHO-hMOR) were purchased from Receptor Biology, Inc. (Baltimore, MD).…”

Section: In Vitro Opioid Receptor Binding and Functional Assaysmentioning

confidence: 99%

JNJ-20788560 [9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic Acid Diethylamide], a Selective Delta Opioid Receptor Agonist, Is a Potent and Efficacious Antihyperalgesic Agent That Does Not Produce Respiratory Depression, Pharmacologic Tolerance, or Physical Dependence

Codd

Carson²,

Colburn³

et al. 2009

J Pharmacol Exp Ther

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ABSTRACT-Opioid analgesics are a mainstay in the treatment of acute and chronic pain of multiple origins, but their side effects, such as constipation, respiratory depression, and abuse liability, adversely affect patients. The recent demonstration of the upregulation and membrane targeting of the ␦-opioid receptor (DOR) following inflammation and the consequent enhanced therapeutic effect of ␦-opioid agonists have enlivened the search for ␦-opioid analgesic agents. JNJ-20788560 [9-(8-azabicyclo-[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide] had an affinity of 2.0 nM for DOR (rat brain cortex binding assay) and a naltrindole sensitive DOR potency of 5.6 nM (5Ј-O-(3-[ 35 S]thio)triphosphate assay). The compound had a potency of 7.6 mg/kg p.o. in a rat zymosan radiant heat test and of 13.5 mg/kg p.o. in a rat Complete Freund's adjuvant RH test but was virtually inactive in an uninflamed radiant heat test.In limited studies, tolerance was not observed to the antihyperalgesic or antinociceptive effects of the compound. Unlike ibuprofen, JNJ-20788560 did not produce gastrointestinal (GI) erosion. Although morphine reduced GI motility at all doses tested and reached nearly full effect at the highest dose, JNJ-20788560 did not retard transit at the lowest dose and reached only 11% reduction at the highest dose administered. Unlike morphine, JNJ-20788560 did not exhibit respiratory depression (blood gas analysis), and no withdrawal signs were precipitated by the administration of opioid ( or ␦) antagonists. Coupled with the previously published lack of self-administration behavior of the compound by alfentanil-trained primates, these findings strongly recommend ␦-opioid agonists such as JNJ-20788560 for the relief of inflammatory hyperalgesia.The -opioid receptor (MOR) is the core target of marketed opioid analgesics, but the side effect profile and abuse liability propensity of these compounds impels the search for better and safer analgesic agents. Although the ␦-opioid receptor (DOR) has long been known to mediate at least a modest level of antinociception (Heyman et al., 1986;Rodriguez et al., 1986), recent work on its regulation during inflammation has provided new impetus to its targeting for the relief of inflammatory pain. Under basal conditions, DOR is located predominantly intracellularly, whereas MOR is localized Article, publication date, and citation information can be found at

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The Novel, Orally Active, Delta Opioid RWJ-394674 Is Biotransformed to the Potent Mu Opioid RWJ-413216

Cited by 14 publications

References 14 publications

Further Studies on Lead Compounds Containing the Opioid Pharmacophore Dmt-Tic

Further Studies on Lead Compounds Containing the Opioid Pharmacophore Dmt-Tic

Delta opioid agonists: a concise update on potential therapeutic applications

JNJ-20788560 [9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic Acid Diethylamide], a Selective Delta Opioid Receptor Agonist, Is a Potent and Efficacious Antihyperalgesic Agent That Does Not Produce Respiratory Depression, Pharmacologic Tolerance, or Physical Dependence

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