Parallel methods for the preparation and SAR exploration of N-ethyl-4-[(8-alkyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-aryl-methyl]-benzamides, powerful mu and delta opioid agonists

Coats, Steven J.; Schulz, Mark J.; Carson, John R.; Codd, Ellen E.; Hlasta, Dennis J.; Pitis, Philip; Stone, Dennis J.; Zhang, Sui‐Po; Colburn, Ray W.; Dax, Scott L.

doi:10.1016/j.bmcl.2004.09.004

Cited by 27 publications

(10 citation statements)

References 16 publications

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“…However, the studies of other DOR agonists [SB-235863, ADL5859 (Le Bourdonnec et al, 2008), ARM390 (http://www.iddb3.com/iddb3/iddb3_2/reports.display? idϭ25779&templateϭDrug&i_query_idϭ10038200), earlier JNJ compounds Coats et al, 2004)] as well as the present investigations with JNJ-20788560 have not revealed proconvulsant effects. Importantly, these several nonproconvulsant DOR agonists comprise diverse structural types, including morphinan, octahydroisoquinoline, tricyclic, and spiro and diarylmethylenepiperidine scaffolds.…”

Section: Comparison Of Treatmentssupporting

confidence: 66%

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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Section: Comparison Of Treatmentssupporting

confidence: 66%

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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“…However, the studies of other DOR-selective agonists have not revealed proconvulsant effects. 67,[70][71][72] It has been pointed out that several non-proconvulsant DOR agonists comprise diverse structural types, including morphinan, octahydroisoquinoline, tricyclic, and spiro and diarylmethylenepiperidine scaffolds, so that DOR agonistinduced convulsions may be the exception rather than the rule. 67 Sleep architecture.…”

mentioning

confidence: 99%

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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“…Series of tropanylidene benzamides synthesized by N-ethyl-4-[(8-phenethyl-8-aza-bicyclo [3.2.1] oct-3-ylidene)-pheny]-methyl]-benzamide (Scheme 13) proved extremely tolerant of structural variation while maintaining excellent opioid activity [8,9]. A subset was tested orally at 150 µmol/kg in the mouse, 48°C hot plate test, some compounds provided robust anti nociception and most induced Straub tail, a behavior often associated with ju opioid agonist activity.…”

Section: Analgesic Activitymentioning

confidence: 99%

Pharmacological Potential of Benzamide Analogues and their Uses in Medicinal Chemistry

Asif¹

2016

Mod Chem Appl

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Benzamide derivatives possess different kinds of pharmacological activities like antimicrobial, analgesic, antiinflammatory, anticancer, cardiovascular, and other biological activities. Due to these biologically significances, scientists have interesting to develop various new benzamide derivatives. There is still need to improve the already used benzamide derivatives and search for the new and more effective benzamide derivatives. This review exhibited various pharmacophoric activities of benzamides analogues which are biologically importance.

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Parallel methods for the preparation and SAR exploration of N-ethyl-4-[(8-alkyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-aryl-methyl]-benzamides, powerful mu and delta opioid agonists

Cited by 27 publications

References 16 publications

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

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

Delta opioid agonists: a concise update on potential therapeutic applications

Pharmacological Potential of Benzamide Analogues and their Uses in Medicinal Chemistry

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