Development of κ opioid receptor antagonists.

@article{Carroll2013DevelopmentO,
  title={Development of $\kappa$ opioid receptor antagonists.},
  author={F. Ivy Carroll and William A. Carlezon},
  journal={Journal of medicinal chemistry},
  year={2013},
  volume={56 6},
  pages={
          2178-95
        }
}
κ opioid receptors (KORs) belong to the G-protein-coupled class of receptors (GPCRs). They are activated by the endogenous opioid peptide dynorphin (DYN) and expressed at particularly high levels within brain areas implicated in modulation of motivation, emotion, and cognitive function. Chronic activation of KORs in animal models has maladaptive effects including increases in behaviors that reflect depression, the propensity to engage in drug-seeking behavior, and drug craving. The fact that… 
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TLDR
κ receptor agonists antagonize the reinforcing/rewarding effects of drugs possibly through punishing/aversive-like effects and reinstate drug seeking through stress- like effects and evidence suggests that abused drugs activate the κ opioid system, which may play a key role in motivational aspects of dependence.
Depressive-Like Effects of the κ-Opioid Receptor Agonist Salvinorin A on Behavior and Neurochemistry in Rats
TLDR
SalvA data provide additional support for the hypothesis that stimulation of brain κ-opioid receptors triggers depressive-like signs in rats and raise the possibility that decreases in extracellular concentrations of DA within the NAc contribute to these effects.
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TLDR
The crystal structure of the mouse δ-OR, bound to the subtype-selective antagonist naltrindole, provides a structural explanation and validation for the ‘message–address’ model of opioid receptor pharmacology, in which distinct ‘ message’ and ‘ address’ determinants are contained within a single ligand.
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TLDR
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TLDR
The current status of KOR signal transduction research is discussed and the data that support two novel hypotheses are discussed: (1) KOR selective partial agonists that do not efficiently activate p38 MAPK may be useful analgesics without producing the dysphoric or hallucinogenic effects of selective, highly efficacious KOR agonists and (2) Kor antagonists thatDo not activate JNK may be effective short-acting drugs that may promote stress-resilience.
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TLDR
These data provide further evidence that stimulation of brain κ-receptors may trigger certain depressive-like signs, and that κ antagonists may have efficacy as antidepressants without having reward-related actions of their own.
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TLDR
HKOR activates p38 MAPK through a phosphorylation and arrestin-dependent mechanism; however, activation differs between hKOR and rKOR for some ligands, which has important implications for preclinical screening of partial KOR agonists.
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TLDR
The findings clearly show that the KOR is involved in mediating the withdrawal aspects of nicotine dependence, and suggest that blockade of the K OR by selective KOR antagonists may be useful smoking cessation pharmacotherapies.
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