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Journal of Medicinal Chemistry Aug 2023A new generation of dual-target μ opioid receptor (MOR) agonist/dopamine D receptor (DR) antagonist/partial agonists with optimized physicochemical properties was...
A new generation of dual-target μ opioid receptor (MOR) agonist/dopamine D receptor (DR) antagonist/partial agonists with optimized physicochemical properties was designed and synthesized. Combining in vitro cell-based on-target/off-target affinity screening, in silico computer-aided drug design, and BRET functional assays, we identified new structural scaffolds that achieved high affinity and agonist/antagonist potencies for MOR and DR, respectively, improving the dopamine receptor subtype selectivity (e.g., DR over DR) and significantly enhancing central nervous system multiparameter optimization scores for predicted blood-brain barrier permeability. We identified the substituted -(2,4)-pyrrolidine and -phenylcyclopropyl amine as key dopaminergic moieties and tethered these to different opioid scaffolds, derived from the MOR agonists () or loperamide (). The lead compounds , , and have the potential of producing analgesic effects through MOR partial agonism with reduced opioid-misuse liability via DR antagonism. Moreover, the peripherally limited derivatives could have therapeutic indications for inflammation and neuropathic pain.
Topics: Humans; Analgesics, Opioid; Dopamine; Ligands; Analgesics; Opioid-Related Disorders; Receptors, Dopamine D3; Receptors, Opioid, mu
PubMed: 37467430
DOI: 10.1021/acs.jmedchem.3c00417 -
Experimental Neurobiology Dec 2023The μ-opioid receptor (MOR) is a class of opioid receptors characterized by a high affinity for β-endorphin and morphine. MOR is a G protein-coupled receptor (GPCR)...
The μ-opioid receptor (MOR) is a class of opioid receptors characterized by a high affinity for β-endorphin and morphine. MOR is a G protein-coupled receptor (GPCR) that plays a role in reward and analgesic effects. While expression of MOR has been well established in neurons and microglia, astrocytic MOR expression has been less clear. Recently, we have reported that MOR is expressed in hippocampal astrocytes, and its activation has a critical role in the establishment of conditioned place preference. Despite this critical role, the expression and function of astrocytic MOR from other brain regions are still unknown. Here, we report that MOR is significantly expressed in astrocytes and GABAergic neurons from various brain regions including the hippocampus, nucleus accumbens, periaqueductal gray, amygdala, and arcuate nucleus. Using the MOR-mCherry reporter mice and Imaris analysis, we demonstrate that astrocytic MOR expression exceeded 60% in all tested regions. Also, we observed similar MOR expression of GABAergic neurons as shown in the previous distribution studies and it is noteworthy that MOR expression is particularly in parvalbumin (PV)-positive neurons. Furthermore, consistent with the normal MOR function observed in the MOR-mCherry mouse, our study also demonstrates intact MOR functionality in astrocytes through iGluSnFr-mediated glutamate imaging. Finally, we show the sex-difference in the expression pattern of MOR in PV-positive neurons, but not in the GABAergic neurons and astrocytes. Taken together, our findings highlight a substantial astrocytic MOR presence across various brain regions.
PubMed: 38196135
DOI: 10.5607/en23039 -
Neuropsychopharmacology : Official... Dec 2023A two-neuron model of ventral tegmental area (VTA) opioid function classically involves VTA GABA neuron regulation of VTA dopamine neurons via a mu-opioid receptor...
A two-neuron model of ventral tegmental area (VTA) opioid function classically involves VTA GABA neuron regulation of VTA dopamine neurons via a mu-opioid receptor dependent inhibitory circuit. However, this model predates the discovery of a third major type of neuron in the VTA: glutamatergic neurons. We found that about one-quarter of VTA neurons expressing the mu-opioid receptor are glutamate neurons without molecular markers of GABA co-release. Glutamate-Mu opioid receptor neurons are largely distributed in the anterior VTA. The majority of remaining VTA mu-opioid receptor neurons are GABAergic neurons that are mostly within the posterior VTA and do not express molecular markers of glutamate co-release. Optogenetic stimulation of VTA glutamate neurons resulted in excitatory currents recorded from VTA dopamine neurons that were reduced by presynaptic activation of the mu-opioid receptor ex vivo, establishing a local mu-opioid receptor dependent excitatory circuit from VTA glutamate neurons to VTA dopamine neurons. This VTA glutamate to VTA dopamine pathway regulated dopamine release to the nucleus accumbens through mu-opioid receptor activity in vivo. Behaviorally, VTA glutamate calcium-related neuronal activity increased following oral oxycodone consumption during self-administration and response-contingent oxycodone-associated cues during abstinent reinstatement of drug-seeking behavior. Further, chemogenetic inhibition of VTA glutamate neurons reduced abstinent oral oxycodone-seeking behavior in male but not female mice. These results establish 1) a three-neuron model of VTA opioid function involving a mu-opioid receptor gated VTA glutamate neuron pathway to VTA dopamine neurons that controls dopamine release within the nucleus accumbens, and 2) that VTA glutamate neurons participate in opioid-seeking behavior.
Topics: Mice; Male; Animals; Ventral Tegmental Area; Analgesics, Opioid; Dopaminergic Neurons; Glutamic Acid; Receptors, Opioid, mu; Oxycodone; Dopamine; gamma-Aminobutyric Acid
PubMed: 37407648
DOI: 10.1038/s41386-023-01637-w -
Neurochemical Research Oct 2023Parkinson's disease is a neurodegenerative disease affecting mainly the elderly population. It is characterized by the loss of dopaminergic neurons of the substantia... (Review)
Review
Parkinson's disease is a neurodegenerative disease affecting mainly the elderly population. It is characterized by the loss of dopaminergic neurons of the substantia nigra pars compacta region. Parkinson's disease patients exhibit motor symptoms like tremors, rigidity, bradykinesia/hypokinesia, and non-motor symptoms like depression, cognitive decline, delusion, and pain. Major pathophysiological factors which contribute to neuron loss include excess/misfolded alpha-synuclein aggregates, microglial cell-mediated neuroinflammation, excitotoxicity, oxidative stress, and defective mitochondrial function. Sigma-1 receptors are molecular chaperones located at mitochondria-associated ER membrane. Their activation (by endogenous ligands or agonists) has shown neuroprotective and neurorestorative effects in various diseases. This review discusses the roles of activated Sig-1 receptors in modulating various pathophysiological features of Parkinson's disease like alpha-synuclein aggregates, neuroinflammation, excitotoxicity, and oxidative stress.
Topics: Aged; Humans; Parkinson Disease; alpha-Synuclein; Neurodegenerative Diseases; Neuroinflammatory Diseases; Dopaminergic Neurons; Substantia Nigra; Sigma-1 Receptor
PubMed: 37259012
DOI: 10.1007/s11064-023-03960-6 -
Neuropsychopharmacology : Official... Aug 2023Opioid withdrawal signs, such as hyperalgesia, are manifestations of opioid use disorder that may contribute to opioid seeking and taking. We have previously identified...
Opioid withdrawal signs, such as hyperalgesia, are manifestations of opioid use disorder that may contribute to opioid seeking and taking. We have previously identified an association between dorsal raphe (DR) neurons and the expression of hyperalgesia during spontaneous heroin withdrawal. Here, we found that chemogenetic inhibition of DR neurons decreased hyperalgesia during spontaneous heroin withdrawal in male and female C57/B6 mice. By neuroanatomy, we identified three major subtypes of DR neurons expressing μ-opioid receptors (MOR) that were activated in hyperalgesia during spontaneous withdrawal, those expressing vesicular GABA transporter (VGaT), glutamate transporter 3 (VGluT3), or co-expressing VGluT3 and tryptophan hydroxylase (TPH). In contrast, we identified a small population of DR-MOR neurons expressing solely TPH, which were not activated in hyperalgesia during spontaneous withdrawal. Collectively, these findings indicate a role of the DR in hyperalgesia during spontaneous heroin withdrawal mediated, in part, by the activation of local MOR-GABAergic, MOR-glutamatergic and MOR-co-releasing glutamatergic-serotonergic neurons. We found that specific chemogenetic inhibition of DR-VGaT neurons blocked hyperalgesia during spontaneous heroin withdrawal in male and female mice. Collectively, these findings indicate that DR-GABAergic neurons play a role in the expression of hyperalgesia during spontaneous heroin withdrawal.
Topics: Mice; Male; Female; Animals; Dorsal Raphe Nucleus; Hyperalgesia; Heroin; Analgesics, Opioid; GABAergic Neurons; Receptors, Opioid, mu
PubMed: 37270620
DOI: 10.1038/s41386-023-01620-5 -
Psychopharmacology Dec 2023Novel synthetic opioids (NSOs) are emerging in recreational drug markets worldwide. In particular, 2-benzylbenzimidazole 'nitazene' compounds are problematic NSOs...
RATIONALE
Novel synthetic opioids (NSOs) are emerging in recreational drug markets worldwide. In particular, 2-benzylbenzimidazole 'nitazene' compounds are problematic NSOs associated with serious clinical consequences, including fatal respiratory depression. Evidence from in vitro studies shows that alkoxy chain length can influence the potency of nitazenes at the mu-opioid receptor (MOR). However, structure-activity relationships (SARs) of nitazenes for inducing opioid-like effects in animal models are not well understood compared to relevant opioids contributing to the ongoing opioid crisis (e.g., fentanyl).
OBJECTIVES
Here, we examined the in vitro and in vivo effects of nitazene analogues with varying alkoxy chain lengths (i.e., metonitazene, etonitazene, isotonitazene, protonitazene, and butonitazene) as compared to reference opioids (i.e., morphine and fentanyl).
METHODS AND RESULTS
Nitazene analogues displayed nanomolar affinities for MOR in rat brain membranes and picomolar potencies to activate MOR in transfected cells. All compounds induced opioid-like effects on locomotor activity, hot plate latency, and body temperature in male mice, and alkoxy chain length markedly influenced potency. Etonitazene, with an ethoxy chain, was the most potent analogue in MOR functional assays (EC = 30 pM, E = 103%) and across all in vivo endpoints (ED = 3-12 μg/kg). In vivo SARs revealed that ethoxy, isopropoxy, and propoxy chains engendered higher potencies than fentanyl, whereas methoxy and butoxy analogues were less potent. MOR functional potencies, but not MOR affinities, were positively correlated with in vivo potencies to induce opioid effects.
CONCLUSIONS
Overall, our data show that certain nitazene NSOs are more potent than fentanyl as MOR agonists in mice, highlighting concerns regarding the high potential for overdose in humans who are exposed to these compounds.
Topics: Rats; Humans; Male; Mice; Animals; Analgesics, Opioid; Fentanyl; Receptors, Opioid, mu
PubMed: 37658878
DOI: 10.1007/s00213-023-06451-2 -
Addiction Neuroscience Dec 2023Opioid use and opioid use disorder are characterized by sex and gender differences, and some of these differences may be mediated by differences in the hormonal milieu...
Opioid use and opioid use disorder are characterized by sex and gender differences, and some of these differences may be mediated by differences in the hormonal milieu within and across individuals. This review focuses on the role of ovarian hormones, and particularly estradiol, on the endogenous mu opioid receptor system. There is an abundance of data indicating that estradiol influences the activity of endogenous mu opioid peptides, the activation of mu opioid receptors, and the internalization and desensitization of mu opioid receptors. These effects have functional consequences on behaviors mediated by endogenous mu opioid receptor activity and on sensitivity to mu opioid agonists and antagonists. Recent behavioral data suggest these consequences extend to mu opioid reward, and preclinical studies report that estradiol decreases self-administration of mu opioid receptor agonists across a range of experimental conditions. Data collected in human laboratory studies suggest that estradiol may have functionally similar effects in clinical populations, and thus estrogen receptors may be a potential target in the development of novel therapeutics. This review summarizes data from cellular assays to clinical trials to explore how estradiol influences mu opioid receptor activity, as well as potential ways in which estrogen receptors may be targeted to address the problems of opioid use.
PubMed: 38155959
DOI: 10.1016/j.addicn.2023.100139 -
Molecular Pharmacology Oct 2023Atypical chemokine receptor 3 (ACKR3) is an arrestin-biased receptor that regulates extracellular chemokine levels through scavenging. The scavenging process restricts...
Atypical chemokine receptor 3 (ACKR3) is an arrestin-biased receptor that regulates extracellular chemokine levels through scavenging. The scavenging process restricts the availability of the chemokine agonist CXCL12 for the G protein-coupled receptor (GPCR) CXCR4 and requires phosphorylation of the ACKR3 C-terminus by GPCR kinases (GRKs). ACKR3 is phosphorylated by GRK2 and GRK5, but the mechanisms by which these kinases regulate the receptor are unresolved. Here we determined that GRK5 phosphorylation of ACKR3 results in more efficient chemokine scavenging and -arrestin recruitment than phosphorylation by GRK2 in HEK293 cells. However, co-activation of CXCR4-enhanced ACKR3 phosphorylation by GRK2 through the liberation of G, an accessory protein required for efficient GRK2 activity. The results suggest that ACKR3 "senses" CXCR4 activation through a GRK2-dependent crosstalk mechanism, which enables CXCR4 to influence the efficiency of CXCL12 scavenging and -arrestin recruitment to ACKR3. Surprisingly, we also found that despite the requirement for phosphorylation and the fact that most ligands promote -arrestin recruitment, -arrestins are dispensable for ACKR3 internalization and scavenging, suggesting a yet-to-be-determined function for these adapter proteins. Since ACKR3 is also a receptor for CXCL11 and opioid peptides, these data suggest that such crosstalk may also be operative in cells with CXCR3 and opioid receptor co-expression. Additionally, kinase-mediated receptor cross-regulation may be relevant to other atypical and G protein-coupled receptors that share common ligands. SIGNIFICANCE STATEMENT: The atypical receptor ACKR3 indirectly regulates CXCR4-mediated cell migration by scavenging their shared agonist CXCL12. Here, we show that scavenging and -arrestin recruitment by ACKR3 are primarily dependent on phosphorylation by GRK5. However, we also show that CXCR4 co-activation enhances the contribution of GRK2 by liberating G. This phosphorylation crosstalk may represent a common feedback mechanism between atypical and G protein-coupled receptors with shared ligands for regulating the efficiency of scavenging or other atypical receptor functions.
Topics: Humans; beta-Arrestins; Chemokine CXCL12; G-Protein-Coupled Receptor Kinases; HEK293 Cells; Ligands; Phosphorylation; Protein Binding; Receptors, CXCR4
PubMed: 37474305
DOI: 10.1124/molpharm.123.000710 -
Trends in Neurosciences Mar 2024Over the past six decades, the use of ketamine has evolved from an anesthetic and recreational drug to the first non-monoaminergic antidepressant approved for... (Review)
Review
Over the past six decades, the use of ketamine has evolved from an anesthetic and recreational drug to the first non-monoaminergic antidepressant approved for treatment-resistant major depressive disorder (MDD). Subanesthetic doses of ketamine and its enantiomer (S)-ketamine (esketamine) directly bind to several neurotransmitter receptors [including N-methyl-d-aspartic acid receptor (NMDAR), κ and μ opioid receptor (KOR and MOR)] widely distributed in the brain and across different cell types, implicating several potential molecular mechanisms underlying the action of ketamine as an antidepressant. This review examines preclinical studies investigating cell-type-specific mechanisms underlying the effects of ketamine on behavior and synapses. Cell-type-specific approaches are crucial for disentangling the critical mechanisms involved in the therapeutic effect of ketamine.
Topics: Humans; Ketamine; Depressive Disorder, Major; Antidepressive Agents; Depression; Brain; Receptors, N-Methyl-D-Aspartate
PubMed: 38220554
DOI: 10.1016/j.tins.2023.12.004 -
Cancers Aug 2023Pancreatic cancer (PDAC) has a poor prognosis despite surgical removal and adjuvant therapy. Additionally, the effects of postoperative analgesia with morphine and...
Pancreatic cancer (PDAC) has a poor prognosis despite surgical removal and adjuvant therapy. Additionally, the effects of postoperative analgesia with morphine and piritramide on survival among PDAC patients are unknown, as are their interactions with opioid/cannabinoid receptor gene expressions in PDAC tissue. Cancer-specific survival data for 71 PDAC patients who underwent radical surgery followed by postoperative analgesia with morphine ( = 48) or piritramide ( = 23) were therefore analyzed in conjunction with opioid/cannabinoid receptor gene expressions in the patients' tumors. Receptor gene expressions were determined using the quantitative real-time polymerase chain reaction. Patients receiving morphine had significantly longer cancer-specific survival (CSS) than those receiving piritramide postoperative analgesia (median 22.4 vs. 15 months; = 0.038). This finding was supported by multivariate modelling ( < 0.001). The morphine and piritramide groups had similar morphine equipotent doses, receptor expression, and baseline characteristics. The opioid/cannabinoid receptor gene expression was analyzed in a group of 130 pancreatic cancer patients. Of the studied receptors, high cannabinoid receptor 2 (CB2) and opioid growth factor receptor (OGFR) gene expressions have a positive influence on the length of overall survival (OS; = 0.029, resp. = 0.01). Conversely, high delta opioid receptor gene expression shortened OS ( = 0.043). Multivariate modelling indicated that high CB2 and OGFR expression improved OS (HR = 0.538, = 0.011, resp. HR = 0.435, = 0.001), while high OPRD receptor expression shortened OS (HR = 2.264, = 0.002). Morphine analgesia, CB2, and OGFR cancer tissue gene expression thus improved CSS resp. OS after radical PDAC surgery, whereas delta opioid receptor expression shortened OS.
PubMed: 37627066
DOI: 10.3390/cancers15164038