scholarly journals Recent Chemical and Pharmacological Developments on 14-Oxygenated-N-methylmorphinan-6-ones

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5677
Author(s):  
Mariana Spetea ◽  
Helmut Schmidhammer
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Opioid Analgesics ◽  
Chronic Administration ◽  
Mu Opioid Receptor ◽  
Receptor Subtype ◽  
Design Strategies ◽  
Mu Opioid ◽  
Multifunctional Ligands

Adequate pain management, particularly chronic pain, remains a major challenge associated with modern-day medicine. Current pharmacotherapy offers unsatisfactory long-term solutions due to serious side effects related to the chronic administration of analgesic drugs. Morphine and structurally related derivatives (e.g., oxycodone, oxymorphone, buprenorphine) are highly effective opioid analgesics, mediating their effects via the activation of opioid receptors, with the mu-opioid receptor subtype as the primary molecular target. However, they also cause addiction and overdose deaths, which has led to a global opioid crisis in the last decades. Therefore, research efforts are needed to overcome the limitations of present pain therapies with the aim to improve treatment efficacy and to reduce complications. This review presents recent chemical and pharmacological advances on 14-oxygenated-N-methylmorphinan-6-ones, in the search of safer pain therapeutics. We focus on drug design strategies and structure–activity relationships on specific modifications in positions 5, 6, 14 and 17 on the morphinan skeleton, with the goal of aiding the discovery of opioid analgesics with more favorable pharmacological properties, potent analgesia and fewer undesirable effects. Targeted molecular modifications on the morphinan scaffold can afford novel opioids as bi- or multifunctional ligands targeting multiple opioid receptors, as attractive alternatives to mu-opioid receptor selective analgesics.

Opioid receptors in the accessory optic system of the rat: Effects of monocular enucleation

1990 ◽  
Vol 5 (5) ◽  
pp. 497-506 ◽  
Author(s):  
R.A. Giolli ◽  
R.H.I. Blanks ◽  
Y. Torigoe ◽  
R.J. Clarke ◽  
J.H. Fallon ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Receptor Binding ◽  
Mu Opioid Receptor ◽  
Mu Opioid Receptors ◽  
Mu Opioid ◽  
Mu Receptor ◽  
Monocular Enucleation ◽  
Mu Receptors ◽  
Opioid Receptor Binding

AbstractThe presence and concentrations of each of the three subtypes of opioid receptors (mu, kappa, and delta) has been studied in the accessory optic nuclei (dorsal, lateral, and medial terminal nuclei and the interstitial nucleus of the superior fasciculus, posterior fibers: DTN, LTN, MTN, and inSFp) in normal young rats with radioligands directed towards each opioid receptor subtype. The changes in mu opioid receptors have also been investigated in monocularly enucleated rats in which one eye was removed and the rats sacrificed at postoperative day (PO) 2, 3, 5, 7, 14, and 30. As the MTN is the only accessory optic nucleus of the rat large enough for semiquantitative evaluation, the mu receptor population of the MTN has been subjected to optical microdensitometric analysis.All four of the accessory optic nuclei (AOS nuclei) are found to contain exceedingly high levels of mu opioid receptor binding with the selective radioligand [3H]-[D-Ala, MePhe4, Gly-ol5] (DAGO), low levels of kappa opioid receptor binding using the radioligand [3H]-[ethylketocyclazocine] (EKC) together with the competing agents [D-Pro4]-morphiceptin and [D-Ser2, Thr6]-Leu-enkephalin, and an absence of delta opioid receptor binding with the radioligand [3H]-[D-A1a2, D-Leu5]-enkephalin (DADLE) combined with the competing agent [D-Pro4]-morphiceptin. Monocular enucleation, as studied on the mu opioid receptor population with this experimental approach, results in virtually a complete loss of mu opioid receptors throughout all four of the contralaterally located AOS nuclei, including both dorsal and ventral subdivisions of the medial terminal nucleus (MTNd, v). Kappa and delta receptors are very few (kappa receptors) or are lacking (delta receptors) in the AOS nuclei, and for this reason, the effects of monocular enucleation on these two opioid receptor subtypes have not been investigated. Monocular enucleation also produces a significant lowering in mu receptor binding in other primary optic nuclei (the lateral geniculate nuclei, nucleus of the optic tract, and superficial layers of the superior colliculus) and in the pars principalis of the medial geniculate nucleus (description of changes in mu receptors in non-accessory optic primary optic nuclei will be considered elsewhere).Microdensitometric study of the MTNd, v shows that the decreased binding of mu receptors in this nucleus is barely detectable (about 6%) at PO2 and rises to 6–15% at PO3. At PO5 receptor loss reaches approximately 62%, whereas at PO7 it is about 81% complete. At PO14 and PO30, the mu receptor loss is nearly complete at around 93%. Mu receptor loss involves all of the AOS nuclei contralateral, but none ipsilateral, to ocular enucleation, an observation entirely consistent with the overwhelmingly crossed (about 97%) nature of the retinofugal projection to the rat accessory optic nuclei. These opioid receptors represent a prominent feature in the AOS and other primary optic nuclei of the rat. Their role in visuomotor control remains uncertain but probably involves the fine-tuning of information concerned with compensatory eye movements.

scholarly journals 6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects

2021 ◽  
Author(s):  
Nicholas S. Akins ◽  
Nisha Mishra ◽  
Hannah M. Harris ◽  
Narendar Dudhipala ◽  
Seong Jong Kim ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Analgesic Activity ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Mu Opioid ◽  
Receptor Agonists ◽  
Opioid Receptor Agonists

Analgesia is commonly mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. Recently, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold <i>via</i> an ester linker. <i>In vitro</i> studies showed that some of these compounds have dual agonism on kappa and mu opioid receptors, while some have triple agonism on kappa, mu, and delta. <i>In vivo </i>studies on the lead dual kappa and mu opioid receptor agonist, compound <b>10</b>, showed that it<b> </b>produced analgesic activity while avoiding anxiogenic effects in murine models, thus providing further strong evidence for the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

Long-term effects of neonatal handling on mu-opioid receptor levels in the brain of the offspring

2009 ◽  
Vol 51 (5) ◽  
pp. 439-449 ◽  
Author(s):  
Georgios Kiosterakis ◽  
Antonios Stamatakis ◽  
Anastasia Diamantopoulou ◽  
Maria Fameli ◽  
Fotini Stylianopoulou
Keyword(s):  
Opioid Receptor ◽  
Mu Opioid Receptor ◽  
Long Term Effects ◽  
Mu Opioid ◽  
Neonatal Handling ◽  
The Brain

scholarly journals GRKs as Key Modulators of Opioid Receptor Function

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2400
Author(s):  
Laura Lemel ◽  
J Robert Lane ◽  
Meritxell Canals
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Opioid Analgesics ◽  
Mu Opioid ◽  
Protein Receptor ◽  
The Family ◽  
Receptor Kinases ◽  
Induced Tolerance ◽  
Shed Light

Understanding the link between agonist-induced phosphorylation of the mu-opioid receptor (MOR) and the associated physiological effects is critical for the development of novel analgesic drugs and is particularly important for understanding the mechanisms responsible for opioid-induced tolerance and addiction. The family of G protein receptor kinases (GRKs) play a pivotal role in such processes, mediating phosphorylation of residues at the C-tail of opioid receptors. Numerous strategies, such as phosphosite specific antibodies and mass spectrometry have allowed the detection of phosphorylated residues and the use of mutant knock-in mice have shed light on the role of GRK regulation in opioid receptor physiology. Here we review our current understanding on the role of GRKs in the actions of opioid receptors, with a particular focus on the MOR, the target of most commonly used opioid analgesics such as morphine or fentanyl.

scholarly journals Heteromerization of Endogenous Mu and Delta Opioid Receptors Induces Ligand-Selective Co-Targeting to Lysosomes

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4493 ◽  
Author(s):  
Lyes Derouiche ◽  
Florian Pierre ◽  
Stéphane Doridot ◽  
Stéphane Ory ◽  
Dominique Massotte
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Acid Ethyl Ester ◽  
Mu Opioid Receptor ◽  
Mu Opioid ◽  
Therapeutic Drugs ◽  
Delta Opioid Receptors ◽  
The Impact ◽  
Fine Tune ◽  
Intracellular Fate

Increasing evidence indicates that native mu and delta opioid receptors can associate to form heteromers in discrete brain neuronal circuits. However, little is known about their signaling and trafficking. Using double-fluorescent knock-in mice, we investigated the impact of neuronal co-expression on the internalization profile of mu and delta opioid receptors in primary hippocampal cultures. We established ligand selective mu–delta co-internalization upon activation by 1-[[4-(acetylamino)phenyl]methyl]-4-(2-phenylethyl)-4-piperidinecarboxylic acid, ethyl ester (CYM51010), [d-Ala2, NMe-Phe4, Gly-ol5]enkephalin (DAMGO), and deltorphin II, but not (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80), morphine, or methadone. Co-internalization was driven by the delta opioid receptor, required an active conformation of both receptors, and led to sorting to the lysosomal compartment. Altogether, our data indicate that mu–delta co-expression, likely through heteromerization, alters the intracellular fate of the mu opioid receptor, which provides a way to fine-tune mu opioid receptor signaling. It also represents an interesting emerging concept for the development of novel therapeutic drugs and strategies.

MU OPIOID RECEPTOR mRNA LEVELS FOLLOWING CHRONIC ADMINISTRATION OF OPIOID LIGANDS

Analgesia ◽  
1995 ◽  
Vol 1 (4) ◽  
pp. 805-808 ◽  
Author(s):  
Ellen M. Unterwald ◽  
Joshua M. Rubenfeld ◽  
Jason Kreuter ◽  
Mary Jeanne Kreek
Keyword(s):  
Opioid Receptor ◽  
Chronic Administration ◽  
Mu Opioid Receptor ◽  
Mrna Levels ◽  
Mu Opioid ◽  
Opioid Ligands ◽  
Receptor Mrna
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