P-Opioid antagonist

The intoxicating effects of opioids appear to be due to their action as agonists on mu (p) receptors of the opioid neurotransmitter system. Competitive p opioid antagonists such as naloxone and naltrexone acutely reverse many of the adverse effects of opioids. To date we do not have specific antagonists for most other abused substances, so rapid pharmacologic reversal of intoxication is usually not possible. 

Mu-Receptor Antagonists Derived from Somatostatin. Potent p-opioid antagonists have been identified that are derivatives of somatostatin rather than of an opioid peptide (see Ref 656 for a review). Somatostatin exhibits low affinity for opioid receptors, and the potent somatostatin analog SMS-201,995 (D-Phe-cycZo[CyS Phe-D-Trp-Lys-Thr-Cys]-Thr-ol) was found to be an antagonist at p, opioid receptors (940). Further structural modification yielded a series of peptides with the general structure D-Phe-cycZo[Cys-Tyr-D-Trp-X-Thr-Pen]-ThrNH, where X = Lys, Om, or Arg in CTP, CTOP (19, Fig. 7.4), and... 

Derrick I, Neilan CL, Andes J, Husbands SM, Woods JH, Traynor JR, Lewis JW (2000) 3-Deoxyclocinnamox the first selective, high affinity, non-peptidic, p-opioid antagonist lacking a phenolic hydroxyl group. J Med Chem 43 3348-3350... 

Inhibition of human multidrug resistance P-glycoprotein 1 was investigated by analogs of a potent. 5-opioid antagonist, including (35, 1 lu5)-3-[(4-hydroxy-2,6-dimethylphenyl)methyl]-11,11 u-dihydro-2//-pyrazino[l, 1-b] isoquinoline-l,4(3//,6//)-dione (OIMIIO). Opioid antagonist activity of... 

Picenadol opioid analgesic (-r)-isomer (3.S,4R) p-receptor agonist (-)-isomer (3R.4.5) weak p-receptor antagonist... 

Opioid systems in the brain are important for the reinforcing effects of ethanol. Selective p-opioid receptor antagonists reliably decrease ethanol drinking in rats. 

A 17 amino acid long peptide sequentially related to opioid peptides in particular dynorphin A. OFQ/N is inactive at the 5, k, and p opioid receptors, but binds to its own NOP receptor (formerly ORL-1, for opioid receptor like-1). In contrast to opioid peptides, OFQ/N has no direct analgesic properties. OFQ/N is the first example for the discovery of a novel neurotransmitter from tissue extracts by using an orphan receptor as bait. Centrally administered in rodents, OFQ/N exerts anxiolytic properties. OFQ/N agonists and antagonists... 

The opioid antagonists naloxone and naltrexone bind to aU three opioid receptors, p, K, and 8. These compounds are antagonists due to their inability to elicit downstream effects of these receptors once bound (Sarton et al. 2008 Yaksh and Rudy 1977). Interestingly, both antagonists have a high binding affinity for MORs. Naloxone is used to reverse the effects of an acute opioid overdose because of its rapid onset of action. Naltrexone elicits similar actions, but has a longer onset and duration of action and hence, is used for the maintenance of treatment for opioid addicts. 

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-... 

Szatmari I, Toth G, Kertesz I, Schiller PW, Borsodi A. Synthesis and binding characteristics of the tritiated TIPP analogue TICP[ P], a highly specific and stable 6 opioid antagonist. Peptides 1999 20 1079-1082. 

Wilkes BC, Schiller, PW. Comparative analysis of various proposed models of the receptor-bound conformation of TIP(P)-related opioid antagonists. Biopolymers (Peptide Sci) 1995 37 391-400. 

Schiller PW, Weltrowska G, Schmidt R, Nguyen, TM-D, Berezowska I, Lemieux C, Chung NN, Carpenter KA, Wilkes BC. Four different types of opioid peptides with mixed p agonist/ antagonist properties. Analgesia 1995 1 703-706. 

Almeida, L.E.P.E., Alkondon, M., Fawcett, E.P., Randall, W.R., Albuquerque, E.X. The opioid antagonist naltrexone inhibits activity and alters expression of alpha7 and alpha4beta2 receptors in hippocampal neurons implications for smoking cessation programs. Neuropharmacology. 39 2740, 2000. 

Opioids also interact with excitatory amino acid neurotransmitters. At lower micromolar concentrations, p agonists (e.g., DAMGO) enhance NMDA activity in the nucleus accumbens, but inhibit non-NMDA activity (Martin et al. 1997). At higher concentrations (5 pM), NMDA currents are reduced. Conversely, central administration of glutamate can precipitate a withdrawal syndrome in morphine-dependent animals, similar to the opioid antagonist naloxone. NMDA mechanisms also appear to be involved in the development of morphine tolerance. Competitive and noncompetitive NMDA antagonists and inhibitors of nitric oxide synthase reduce or eliminate tolerance to morphine (Elliott et al. 1995 Bilsky et al. 1996). However, this does not occur for tolerance to k opioids. Pharmacokinetics... 

There is also evidence for cholinergic involvement in caffeine analgesia (Ghelardini et al. 1997). The muscarinic antagonists atropine and pirenzepine, and the choline uptake inhibitor hemicholinium-3 prevent caffeine analgesia. In contrast, it was unaffected by an opioid antagonist (naloxone) or a tyrosine hydroxylase inhibitor (o-methyl-p-tyrosine). 

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