Receptors, opioids

The two /3-turn structures, pc and Pe are the most stable among those considered. This is in accord with the unconstrained nanosecond simulations of linear DPDPE, which converged to these conformers [14]. Because the cyclic form is relatively rigid, it is assumed that the conformation it adopts in solution is the biologically active one, responsible for its high affinity and specificity towards the 5 opioid receptor. The relatively low population of the cyclic-like structure for the linear peptide thus agrees qualitatively with the... 

The opioid peptides vary in their binding affinities for the multiple opioid receptor types. Leu- and Met-enkephalin have a higher affinity for 5-receptors than for the other opioid receptor types (68), whereas the dynorphin peptides have a higher affinity for K-sites (69). P-Endorphin binds with equal affinity to both p- and 5-receptors, but binds with lower affinity to K-sites (70). The existence of a P-endorphin-selective receptor, the S-receptor, has been postulated whether this site is actually a separate P-endorphin-selective receptor or is a subtype of a classical opioid receptor is a matter of controversy (71,72). The existence of opioid receptor subtypes in general is quite controversial although there is some evidence for subtypes of p- (73), 5-(74), and K-receptors (72,75), confirmation of which may be obtained by future molecular cloning studies. 

Fig. 5. Schematic diagram of the presumed arrangement of the amino acid sequence for the 5-opioid receptor, showing seven putative transmembrane segments three intracellular loops, A three extracellular loops, B the extracellular N-terrninus and the intracellular C-terrninus, where (0) represents amino acid residues common to ] -, 5-, and K-receptors ( ), amino acid residues common to all three opioid receptors and other neuropeptide receptors and (O), other amino acids. Branches on the N-terruinal region indicate possible glycosylation sites, whereas P symbols in the C-terminal region indicate...

Dynorphin may also influence nociception at the spinal level. The levels of prodynorphin mRNA and immunoreactive dynorphin increase in the chronic inflammatory arthritic model (158). Dynorphin also inhibits morphine or P-endorphin-induced analgesia in naive animals and enhances analgesia in tolerant animals, indicating that this peptide may have a regulatory role in opioid analgesia (159). This effect does not appear to be mediated by a classical opioid receptor, since des-tyrosine dynorphin, which does not bind to opioid receptors, also antagonizes morphine analgesia (160). 

In an approach to opioid receptor ligands,diazabicyclononanones were prepared in a double Petrenko-Kritschenko reaction. Diester 76, in the presence of methylamine and aryl aldehydes, was converted to piperidone 77. This was immediately resubmitted to the reaction conditions however, in this iteration formaldehyde replaced the aryl aldehyde component. The outcome of this reaction produced 78 which was further investigated for its use in rheumatoid arthritis. 

Ligand recognition in the opioid receptors by modeling methods and design of opioids 98YZ1. 

Costa, T., and Herz, A. (1989). Antagonists with negative intrinsic activity at 6-opioid receptors coupled to GTP-binding proteins. Proc. Natl. Acad. Sci. U.S.A. 86 7321-7325. 

FIGURE 9.19 Dimeric antagonist formed by oligoglycyl-based linkage of two opioid receptor subtype antagonists naltrindole and ICI-199,441. From [59],... 

Opioids act on heptahelical G-protein-coupled receptors. Three types of opioid receptors (p, 8, k) have been cloned. Additional subtypes (e.g., pl3 p2, 81 82), possibly resulting from gene polymorphisms, splice variants or alternative processing have been proposed. Opioid receptors are localized and can be activated... 

Opioids ( opioid systems) are thought to exert their antitussive effects by acting as agonists at p- and K-opioid receptors in the CNS. Activation of these receptors activates various G-proteins and leads to the inhibition of... 

Opiate overdose is a medical emergency that can result in respiratory and CNS depression. The opioid receptor antagonist naloxone immediately reverses cardiorespiratory depression. However, repeated naloxone administration is required, since the effects of naloxone last for 30 min, while opioid agonists can remain at potentially lethal blood levels for several hours. 

The pharmacological and/or adverse effects of a drug can be reversed by co-administration of drugs which compete for the same receptor. For example, an opioid receptor antagonist naloxone is used to reverse the effects of opiates. Drugs acting at the same site with opposite effects also can affect each other, e.g. the reduction in the anticoagulant effect of warfarin by vitamin K. 

Cytotoxics cause an elevation of dopamine levels in the area postrema in animal studies and may release prostaglandins and inhibit enzymes such as enkepha-linases to allow increased levels of enkephalins to activate opioid receptors on dopaminergic nerves. 

Endogenous opioid peptides are the wide variety of endogenous peptides isolated since 1975 which are the natural ligands for the opioid receptors. The peptides... 

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

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