ICI 204448: a κP‐opioid agonist with limited access to the CNS

Shaw, John S.; Carroll, Jacqueline A.; Alcock, Peter; Main, Brian G.

doi:10.1111/j.1476-5381.1989.tb11911.x

Cited by 75 publications

(49 citation statements)

References 19 publications

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“…Thirty mg kg-' ICI 204448 s.c. produced no reduction in DOPA accumulation in the nucleus accumbens ( Table 2) or prolongation of hexobarbitone-induced sleeping (Table 2), and 100 mg kg-' ICI 204448 s.c. did not impair motor performance in the rotarod test (Table 2). Since ICI 204448 is as potent in the rabbit vas deferens assay as the other ic agonists used here it is likely that these results are indicative of poor penetration into the CNS due to the polar zwitterionic stucture of ICI 204448 (Shaw et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

“…These findings, along with the recognition that the systemic application of such agonists in humans has unacceptable central side effects (Pfeiffer et al, 1986), have led to interest in the development of 'peripherally-selective' K-opioid receptor agonists for the treatment of inflammatory hyperalgesia. EMD 60400 (Barber et al, 1992), ICI 197067 (Costello et al, 1988) and ICI 204448 (Shaw et al, 1989) peridol is known to be reversed by centrally-active Kc-opioid receptor agonists (Manzanares et al, 1991) because dopamine release in the accumbens is also subject to presynaptic inhibition from K agonists (Smith et al, 1992). Since the 1K agonists used here have only very poor affinity for dopamine receptors (C.A.…”

Section: Discussionmentioning

confidence: 99%

“…Ex vivo determination of brain and plasma levels These assays were performed as described by Shaw et al (1989) with a few modifications. Briefly, groups of six female NMRI mice (22-24 g) were injected with vehicle, or test compound dissolved in saline.…”

Section: Tests For Demonstrating Central Actions Of K Agonistsmentioning

confidence: 99%

“…penetrates the blood-brain barrier (Shaw et al, 1989). Our aim was to investigate whether EMD 60400 can have peripherally-mediated actions at systemic doses which do not produce centrally-mediated side effects.…”

Section: Introductionmentioning

confidence: 99%

“…Evidence has recently ICI 197067. ICI 204448 (Shaw et al, 1989) is a K-opioid become available that opiates can also have peripheral antireceptor agonist which has been described as having only nociceptive actions, in particular when inflammation is preslimited access to the CNS, though there have been few tests ent (see , for recent review). An of its antinociceptive effectiveness in animal models of pain Rogers et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

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Central and peripheral actions of the novel κ‐opioid receptor agonist, EMD 60400

Barber

Bartoszyk

Greiner

et al. 1994

British J Pharmacology

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1 The pharmacological characteristics of the x-opioid receptor agonist, EMD 60400, have been investigated, with particular reference to its central and peripheral sites of action and its ability to influence nociception. The K agonists ICI 197067 and ICI 204448 10 Pharmacological and biochemical data therefore indicate that the three K-opioid receptor agonists tested here have different tendencies to elicit centrally-mediated sedation and putative aversion (ICI 197067 > EMD 60400 > ICI 204448) which correspond to their ability to cross the blood-brain barrier. EMD 60400 combines high affinity and selectivity for the K receptor with a degree of peripheral selectivity. The peripheral actions of systemically-applied EMD 60400 against hyperalgesic pressure pain and neurogenic inflammation are very probably mediated by opioid receptors on the endings of sensory nerve fibres.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Tests For Demonstrating Central Actions Of K Agonistsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Central and peripheral actions of the novel κ‐opioid receptor agonist, EMD 60400

Barber

Bartoszyk

Greiner

et al. 1994

British J Pharmacology

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Characterization of Opioid and ORL1 Receptors

et al. 2005

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This unit describes methods for studying activity at opioid receptor subtypes and the ORL1 receptor using conventional radioligand binding assay methods as well as procedures for quantitating functional activity of these receptors by measuring agonist‐induced G protein activation with [35S]GTPγS binding in a manner analogous to traditional receptor‐binding methods. These procedures permit the assessment of the agonist or antagonist character of compounds in a rapid manner that, like most radioligand binding methodologies, is also amenable to high throughput technologies.

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Narcotic Analgesics

Aldrich

Vigil‐Cruz

2003

Burger's Medicinal Chemistry and Drug Discovery

147

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Narcotic analgesics such as morphine have been the mainstay for the treatment of severe pain, although these drugs are associated with serious adverse effects, most notably addiction liability and respiratory depression. Therefore there has been an intensive effort to find new therapeutic agents that retain the effectiveness of morphine, but do not have its undesired side effects. Compounds have been identified from a wide variety of chemical classes, from the rigid morphinan alkaloids to the flexible phenylpiperidines and the opioid peptides, which have affinity for opioid receptors. In recent years considerable effort has focused on identifying ligands, both agonists and antagonists, with affinity for delta (δ) and kappa (κ) opioid receptors as pharmacological tools and as potential therapeutic agents that would not have the side‐effect profile of morphine and other agonists that interact with mu (μ) opioid receptors. After the identification of the closely related opioid receptor‐like (ORL1) receptor and its endogenous ligand orphanin FQ/nociceptin, there has been considerable effort directed toward identifying agonists and antagonists for this receptor as well. This review discusses the structure‐activity relationships for each of the major classes of compounds that interact with the opioid receptors, along with ligands for the ORL1 receptors.

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ICI 204448: a κP‐opioid agonist with limited access to the CNS

Cited by 75 publications

References 19 publications

Central and peripheral actions of the novel κ‐opioid receptor agonist, EMD 60400

Central and peripheral actions of the novel κ‐opioid receptor agonist, EMD 60400

Characterization of Opioid and ORL1 Receptors

Narcotic Analgesics

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