P-opioid agonists

Bohn LM, Belcheva MM, Coscia CJ (2000) p-opioid agonist inhibition of kappa-opioid receptor-stimulated extracellular signal-regulated kinase phosphorylation is dynamin-dependent in C6 glioma cells. J Neurochem 74 574-581... 

Regulation of Neuronal Chemoldne Receptor CXCR4 by p-Opioid Agonists... 

The three prototype mixed p agonist/S antagonists described in this chapter have excellent potential as analgesics with low propensity to produce tolerance and dependence. The pseudotetrapeptide DIPP-NH2[ ] has already been shown to produce a potent analgesic effect, less tolerance than morphine, and no physical dependence upon chronic administration. In preliminary experiments, the tetrapeptides DIPP-NH2 and DIPP-NH2[T] were shown to cross the BBB to some extent, but further structural modifications need to be performed in order to improve the BBB penetration of these compounds. The Tyr-Tic dipeptide derivatives can also be expected to penetrate into the central nervous system because they are relatively small, lipophilic molecules. In this context, it is of interest to point out that the structurally related dipeptide H-Dmt-D-Ala-NH-(CH2)3-Ph (SC-39566), a plain p-opioid agonist, produced antinociception in the rat by subcutaneous and oral administration [72], As indicated by the results of the NMR and molecular mechanics studies, the conformation of the cyclic p-casomorphin analogue H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] is stabilized by intramolecular hydrogen bonds. There-... 

Potent anti nociception and reduced side-effects through the combination of p-opioid agonists with L-type Ca2+ channel antagonists... 

Respiratory depression is one of the most prominent adverse effects of p opioid agonists (e.g., morphine). The frequency of breathing and the inspiratory volume can be affected differently by drugs and have to be measured. 

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. 

Delta Receptors. There has been considerable interest in 6 opioid agonists because they exhibit antinociceptive effects without the side effects associated with p, opioid receptor agonists. Antinociceptive activity was first demonstrated with 6-selective opioid peptides (see Ref 218 for a review), and more recently with nonpeptidic 6-selective agonists (see Refs. 219-222 for reviews). Of particular interest is the activity of 6 agonists in inflammatory and neuropathic pain (220). Delta opioid receptors also modulate fx opioid receptors and, as discussed earlier, one classification of 6 opioid receptor subtypes was based on their association with p, opioid receptors. There is now considerable evidence that interaction between the two receptor types can alter the activity of p. opioid agonists. Delta agonists... 

Portoghese and Suzuki have studied the possibility of reducing the undesirable side effects of p opioid agonists by combining them with a 8 opioid antagonist. This concept is based on the cross-talk among all three types of opioid receptors. 

In vivo, introduction of a methyl group in position 5 in 14-O-methyloxymor-phone (48) resulted in somewhat of a decrease in antinociceptive potency, i.e. 5-fold in the hot-plate test (Table 2) and 2-fold in the tail-flick test in mice after s.c. administration for compound 62 [67]. Pharmacological studies consistently reported on the high antinociceptive activity of the p-opioid agonist 62 ranging between 24- and 20,000-fold in comparison to morphine in diverse models of acute nociception (i.e. hot-plate test [44, 47, 71], tail-flick test [44, 67, 73, 76, 79] and tail electrical stimulation test [72]), and visceral pain (acetic acid- [69, 79], and... 

Zemig G, Saria A, Krassnig R, Schmidhammer H (2000) Signal transduction efficacy of the highly potent p-opioid agonist 14-methoxymetopon. Life Sci 66 1871-1877... 

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