K Opioid Agonists

In further support of a pro-nociceptive role of CX3CL1 are data showing that the direct injection of CX3CL1 in the periaqueductal grey, a brain region mostly involved with analgesic responses, albeit un-effective by itself, results in inhibition of the antinociceptive effects induced by p, 5, and k opioid agonists (Chen et al. 2(X)7). 

Rothman R., France C., Bykov V. et al. Pharmacological activities of optically pure enantiomers of the K opioid agonist, U50,488 and its els diastereomer evidence for three K receptor subtypes. Em J. Pharmacol. 167 345, 1989. 

Scheme 1 Selective K-opioid agonists and norbinaltorphimine (antagonist).

Idanpaan, J. J., Kalso, E. A., Seppala, T.. Antinociceptive actions of dexmedetomidine and the K-opioid agonist U-50488H against noxious thermal, mechanical and inflammatory stimuli, J. Pharmacol. Exp. Ther. 1994, 271, 1306-1313. 

Garaulet, J.V., Laorden, M.L., Milanes, M.V. Effect of chronic administration of dihydropyridine Ca2+ channel ligands on sufentanil-induced tolerance to p- and K-opioid agonists in the guinea pig ileum myenteric plexus, Regulatory Peptides 1996, 63, 1-8. 

The so far unsuccessful attempts towards the development of selective K-opioid agonists are summarised in Chapter 3.1. Clinically relevant opioids with affinity to the tc-opioid receptor are discussed in Chapter 3.4. 

Elevation in spinal dynorphin content has also been seen in condition of opioid-induced pain state (Vanderah et al., 2000). Although dynorphine was originally identified as an endogenous K-opioid agonist and may act as an endogenous antinociceptive peptide under certain conditions, considerable... 

Campi CC, Clarke GD (1995) Effects of highly selective k-opioid agonists on EEG power spectra and behavioral correlates in conscious rats. Pharmacol Biochem Behav 51 611-616... 

Three animals are used for the test compound and the standard. Dose-response curves of the effect on respiratory frequency and volume are compared. While p, opioid agonists decrease respiratory function, k opioid agonist either increase or have no effect on respiratory function. The magnitude of respiratory depression produced by p, opioid agonists is related to their efficacy at opioid receptors with low efficacy agonists such as nalbuphine having much less effect on respiration as compared to morphine. 

Shippenberg TS, Herz A (1987) Place preference conditioning reveals the involvement of Di -dopamine receptors in the motivational properties of. i- and K-opioid agonists. Brain Res 436 169-172... 

Ca -induced seizures (264). The drug is structurally related to a K-opioid agonist, although it shows no binding affinity to this receptor. Its primary effect is with sodium channels it blocks NlE-115 mouse neuroblastoma cells in a voltage- and use-dependent manner... 

Kappa Receptors. Like jx and 6 receptors, activation of k opioid receptors can produce antinociceptive effects. However, the effectiveness of k opioid agonists as antinociceptive agents varies in different types of pain (see Ref 146), and k agonists are less effective in thermal antinociceptive assays involving more intense stimuli. 

The effects of k opioid agonists on dopamine levels also has implications for the treatment of cocaine abuse. Cocaine blocks reuptake of dopamine, and considerable evidence suggests that cocaine s reinforcing effects are mediated by these increases in extracellular dopamine (see Refs. 250, 251 and references cited therein). Because k agonists can decrease dopamine levels, they can ad as functional antagonists of cocaine (250, 251). Several k agonists have been shown to decrease cocaine selfadministration (250-254 but see Ref 255) and K agonists can also attenuate many of the behavioral effects of cocaine (see Ref 250). 

D-Pharmacophore Identification for K-Opioid Agonists Using Ligand-Based Drug-Design Techniques... 

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