The Role of the Side Chain in Determining Relative δ- and κ-Affinity in C5‘-Substituted Analogues of Naltrindole

Black, Shannon L.; Jales, Andrew R.; Brandt, Wolfgang; Lewis, John W.; Husbands, Stephen M.

doi:10.1021/jm020997b

Cited by 17 publications

(11 citation statements)

References 16 publications

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“…4A). The order of potency for norBNI was κ > δ > μ, although it must be noted that there was no effect of norBNI on DAMGO-stimulated GTPyS coupling, with these data consistent with previous reports (Black, Jales, Brandt, Lewis, & Husbands, 2003; Takemori, Ho, Naeseth, & Portoghese, 1988). Conversely, zyklophin (5.0 µM) significantly stimulated GTPyS coupling in rat brain tissue (Fig.…”

Section: Discussionsupporting

confidence: 91%

Species differences in the effects of the κ-opioid receptor antagonist zyklophin

Sirohi

Aldrich

Walker

2016

Alcohol

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We have shown that dysregulation of the dynorphin/kappa-opioid receptor (DYN/KOR) system contributes to escalated alcohol self-administration in alcohol dependence and that KOR antagonists with extended durations of action selectively reduce escalated alcohol consumption in alcohol-dependent animals. As KOR antagonism has gained widespread attention as a potential therapeutic target to treat alcoholism and multiple neuropsychiatric disorders, we tested the effect of zyklophin (a short-acting KOR antagonist) on escalated alcohol self-administration in rats made alcohol-dependent using intermittent alcohol vapor exposure. Following dependence induction, zyklophin was infused centrally prior to alcohol self-administration sessions and locomotor activity tests during acute withdrawal. Zyklophin did not impact alcohol self-administration or locomotor activity in either exposure condition. To investigate the neurobiological basis of this atypical effect for a KOR antagonist, we utilized a κ-, μ-, and δ-opioid receptor agonist-stimulated GTPyS coupling assay to examine the opioid receptor specificity of zyklophin in the rat brain and mouse brain. In rats, zyklophin did not affect U50488-, DAMGO-, or DADLE-stimulated GTPyS coupling, whereas the prototypical KOR antagonist nor-binaltorphimine (norBNI) attenuated U50488-induced stimulation in the rat brain tissue at concentrations that did not impact μ- and δ-receptor function. To reconcile the discrepancy between the present rat data and published mouse data, comparable GTPyS assays were conducted using mouse brain tissue; zyklophin effects were consistent with KOR antagonism in mice. Moreover, at higher concentrations, zyklophin exhibited agonist properties in rat and mouse brains. These results identify species differences in zyklophin efficacy that, given the rising interest in the development of short-duration KOR antagonists, should provide valuable information for therapeutic development efforts.

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Section: Discussionsupporting

confidence: 91%

Species differences in the effects of the κ-opioid receptor antagonist zyklophin

Sirohi

Aldrich

Walker

2016

Alcohol

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“…[2][3][4][5] So far, 11 C labeling of ureas in the carbonyl function has been performed mainly starting from [ 11 C]phosgene. In this paper, an efficient synthesis of [ 11 C]ureas via triphenylphosphinimines and [ 11 C]CO 2 is described.…”

Section: Introductionmentioning

confidence: 99%

One‐pot synthesis of [¹¹C]ureas via triphenylphosphinimines

Tilburg

Windhorst

Mey

et al. 2006

Labelled Comp Radiopharmac

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“…4) for the κ receptor. The high basicity of guanidines and amidines supports the concept that a charged basic group attached at the 5' position is a requirement for potent κ antagonist activity [62][63][64][65][66][67].…”

Section: Gntimentioning

confidence: 81%

Kappa Receptor Bivalent Ligands

Peng

Neumeyer²

2007

CTMC

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Bivalent ligands of kappa opioid agonists and antagonists, such as norBNI and BNI, are used as tools to elucidate the kappa receptor characteristics. Bivalent ligands may also be effective analgesics although none have this far been used clinically. Structure-activity relationships (SAR) and molecular modeling led to the development of a more potent and selective kappa antagonist (5'-guanidinylnaltrindole, GNTI). Novel homo and hetero bivalent ligands with high mixed kappa/micro or mixed kappa/delta affinity and intriguing pharmacological properties may eventually lead to useful analgesics with fewer adverse side effects. Bivalent ligands were also developed that could act as probes of the receptor-oligomerzation and organization phenomena. A structurally unique kappa antagonist (JDTic) provides an additional tool to characterize kappa opioid receptor.

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The Role of the Side Chain in Determining Relative δ- and κ-Affinity in C5‘-Substituted Analogues of Naltrindole

Cited by 17 publications

References 16 publications

Species differences in the effects of the κ-opioid receptor antagonist zyklophin

Species differences in the effects of the κ-opioid receptor antagonist zyklophin

One‐pot synthesis of [¹¹C]ureas via triphenylphosphinimines

Kappa Receptor Bivalent Ligands

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The Role of the Side Chain in Determining Relative δ- and κ-Affinity in C5‘-Substituted Analogues of Naltrindole

Cited by 17 publications

References 16 publications

Species differences in the effects of the κ-opioid receptor antagonist zyklophin

Species differences in the effects of the κ-opioid receptor antagonist zyklophin

One‐pot synthesis of [11C]ureas via triphenylphosphinimines

Kappa Receptor Bivalent Ligands

Contact Info

Product

Resources

About

One‐pot synthesis of [¹¹C]ureas via triphenylphosphinimines