Tuning Down the Pain – An Overview of Allosteric Modulation of Opioid Receptors: Mechanisms of Modulation, Allosteric Sites, Modulator Syntheses

2020 ◽  
Vol 20 (31) ◽  
pp. 2852-2865 ◽  
Author(s):  
Damian Bartuzi ◽  
Tomasz M. Wróbel ◽  
Agnieszka A. Kaczor ◽  
Dariusz Matosiuk
Keyword(s):  
Side Effects ◽  
Opioid Receptors ◽  
Pain Perception ◽  
Allosteric Modulation ◽  
Allosteric Modulators ◽  
Signaling Mechanisms ◽  
Main Target ◽  
Allosteric Sites ◽  
Biased Signaling ◽  
Opioid Signaling

Opioid signaling plays a central role in pain perception. As such, it remains the main target in the development of antinociceptive agents, despite serious side effects involved. In recent years, hopes for improved opioid painkillers are rising, together with our understanding of allosterism and biased signaling mechanisms. In this review, we focus on recently discovered allosteric modulators of opioid receptors, insights into phenomena underlying their action, as well as on how they extend our understanding of mechanisms of previously known compounds. A brief overlook of their synthesis is also presented.

scholarly journals Identification of Selective Agonists and Positive Allosteric Modulators for µ- and δ-Opioid Receptors from a Single High-Throughput Screen

2014 ◽  
Vol 19 (9) ◽  
pp. 1255-1265 ◽  
Author(s):  
Neil T. Burford ◽  
Tom Wehrman ◽  
Daniel Bassoni ◽  
Jonathan O’Connell ◽  
Martyn Banks ◽  
...  
Keyword(s):  
Opioid Receptors ◽  
High Throughput ◽  
Allosteric Modulators ◽  
High Throughput Screen ◽  
Selective Ligand ◽  
Selective Ligands ◽  
Allosteric Sites ◽  
Selective Agonists ◽  
Positive Allosteric Modulators ◽  
Δ Opioid Receptor

Hetero-oligomeric complexes of G protein–coupled receptors (GPCRs) may represent novel therapeutic targets exhibiting different pharmacology and tissue- or cell-specific site of action compared with receptor monomers or homo-oligomers. An ideal tool for validating this concept pharmacologically would be a hetero-oligomer selective ligand. We set out to develop and execute a 1536-well high-throughput screen of over 1 million compounds to detect potential hetero-oligomer selective ligands using a β-arrestin recruitment assay in U2OS cells coexpressing recombinant µ- and δ-opioid receptors. Hetero-oligomer selective ligands may bind to orthosteric or allosteric sites, and we might anticipate that the formation of hetero-oligomers may provide novel allosteric binding pockets for ligand binding. Therefore, our goal was to execute the screen in such a way as to identify positive allosteric modulators (PAMs) as well as agonists for µ, δ, and hetero-oligomeric receptors. While no hetero-oligomer selective ligands were identified (based on our selection criteria), this single screen did identify numerous µ- and δ-selective agonists and PAMs as well as nonselective agonists and PAMs. To our knowledge, these are the first µ- and δ-opioid receptor PAMs described in the literature.

Steroids as the novel class of high-affinity allosteric modulators of muscarinic receptors

2021 ◽  
Author(s):  
Eva Dolejší ◽  
Eszter Szánti-Pintér ◽  
Nikolai Chetverikov ◽  
Dominik Nelic ◽  
Alena Randáková ◽  
...  
Keyword(s):  
Muscarinic Receptors ◽  
Acetylcholine Receptors ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Allosteric Modulators ◽  
The Novel ◽  
Stress Control ◽  
Structure Activity ◽  
G Protein Coupled

Abstract The membrane cholesterol was found to bind and modulate the function of several G-protein coupled receptors including muscarinic acetylcholine receptors. We investigated the binding of 20 steroidal compounds including neurosteroids and steroid hormones to muscarinic receptors. Corticosterone, progesterone, and some neurosteroids bound to muscarinic receptors with an affinity of 100 nM or greater. We established a structure-activity relationship for steroid-based allosteric modulators of muscarinic receptors. Further, we show that corticosterone and progesterone allosterically modulate the functional response of muscarinic receptors to acetylcholine at physiologically relevant concentrations. It can play a role in stress control or in pregnancy, conditions where levels of these hormones dramatically oscillate. Allosteric modulation of muscarinic receptors via the cholesterol-binding site represents a new pharmacological approach at diseases associated with altered cholinergic signalling.

scholarly journals POST-OPERATIVE PAIN RELIEF FOR LOWER ABDOMINAL SURGERY

2005 ◽  
Vol 12 (03) ◽  
pp. 340-345
Author(s):  
ROBINA FIRDOUS
Keyword(s):  
Pain Management ◽  
Side Effects ◽  
Pain Relief ◽  
Abdominal Surgery ◽  
Opioid Receptors ◽  
Acute Pain ◽  
Alternate Route ◽  
Parenteral Route ◽  
Group I ◽  
Post Operative Pain

The severity of post-operative pain and the lack of efforts in relievingit have led to the involvement of Anaesthesiologists in the management of post-operative and acute pain. Parenteralopiates have been utilized for post-operative pain management. The identification of the opioid receptors on substantiagelatinosa has provided an alternate route i.e 1 the epidural route - for administering opiates. Objectives: To evaluateand compare the efficacy and side effects of parenteral Buprenorphine with those of Extradural Buprenorphine.Setting: Department of Anaesthesia, District Headquarter Hospital, Faisalabad. Period: The data was collected duringthe last three and a half years. Materials and Methods: Sixty adult patients of either sex and ages ranging from 35-45years, who underwent lower abdominal surgery, were randomly selected for the study. They were equally divided intotwo groups. Group I patients were administered Buprenorphine 0.3 mg through the epidural catheter in extraduralspace. Group II patients were given Buprenorphine 0.3 mg intramuscularly. Results: Buprenorphine through theepidural route gives better analgesia with fewer side effects as compared with the parenteral route.

scholarly journals Widespread Changes in Positive Allosteric Modulation of the Muscarinic M1 Receptor in Some Participants With Schizophrenia

2019 ◽  
Vol 22 (10) ◽  
pp. 640-650 ◽  
Author(s):  
Shaun Hopper ◽  
Geoffrey Mark Pavey ◽  
Andrea Gogos ◽  
Brian Dean
Keyword(s):  
Carboxylic Acid ◽  
Radioligand Binding ◽  
Allosteric Modulation ◽  
Allosteric Modulator ◽  
Allosteric Modulators ◽  
Positive Allosteric Modulator ◽  
M1 Receptor ◽  
Area 6 ◽  
Subcortical Regions

Abstract Background Preclinical and some human data suggest allosteric modulation of the muscarinic M1 receptor (CHRM1) is a promising approach for the treatment of schizophrenia. However, it is suggested there is a subgroup of participants with schizophrenia who have profound loss of cortical CHRM1 (MRDS). This raises the possibility that some participants with schizophrenia may not respond optimally to CHRM1 allosteric modulation. Here we describe a novel methodology to measure positive allosteric modulation of CHRM1 in human CNS and the measurement of that response in the cortex, hippocampus, and striatum from participants with MRDS, non-MRDS and controls. Methods The cortex (Brodmann’s area 6), hippocampus, and striatum from 40 participants with schizophrenia (20 MRDS and 20 non-MRDS) and 20 controls were used to measure benzyl quinolone carboxylic acid-mediated shift in acetylcholine displacement of [3H]N-methylscopolamine using a novel in situ radioligand binding with autoradiography methodology. Results Compared with controls, participants with schizophrenia had lower levels of specific [3H]N-methylscopolamine binding in all CNS regions, whilst benzyl quinolone carboxylic acid-modulated binding was less in the striatum, Brodmann’s area 6, dentate gyrus, and subiculum. When divided by subgroup, only in MRDS was there lower specific [3H]N-methylscopolamine binding and less benzyl quinolone carboxylic acid-modulated binding in all cortical and subcortical regions studied. Conclusions In a subgroup of participants with schizophrenia, there is a widespread decreased responsiveness to a positive allosteric modulator at the CHRM1. This finding may have ramifications it positive allosteric modulators of the CHRM1 are used in clinical trials to treat schizophrenia as some participants may not have an optimal response.

scholarly journals Proposed Mode of Binding and Action of Positive Allosteric Modulators at Opioid Receptors

2016 ◽  
Vol 11 (5) ◽  
pp. 1220-1229 ◽  
Author(s):  
Yi Shang ◽  
Holly R. Yeatman ◽  
Davide Provasi ◽  
Andrew Alt ◽  
Arthur Christopoulos ◽  
...  
Keyword(s):  
Opioid Receptors ◽  
Allosteric Modulators ◽  
Positive Allosteric Modulators

scholarly journals Antinociceptive Effects of Cardamonin in Mice: Possible Involvement of TRPV1, Glutamate, and Opioid Receptors

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2237 ◽  
Author(s):  
Chung Ping ◽  
Tengku Tengku Mohamad ◽  
Muhammad Akhtar ◽  
Enoch Perimal ◽  
Ahmad Akira ◽  
...  
Keyword(s):  
Side Effects ◽  
Opioid Receptors ◽  
Warning Sign ◽  
Antinociceptive Effects ◽  
Sedative Effects ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Hospital Visits ◽  
Dose Dependent ◽  
Thermal Stimuli

Pain is one of the most common cause for hospital visits. It plays an important role in inflammation and serves as a warning sign to avoid further injury. Analgesics are used to manage pain and provide comfort to patients. However, prolonged usage of pain treatments like opioids and NSAIDs are accompanied with undesirable side effects. Therefore, research to identify novel compounds that produce analgesia with lesser side effects are necessary. The present study investigated the antinociceptive potentials of a natural compound, cardamonin, isolated from Boesenbergia rotunda (L) Mansf. using chemical and thermal models of nociception. Our findings showed that intraperitoneal and oral administration of cardamonin (0.3, 1, 3, and 10 mg/kg) produced significant and dose-dependent inhibition of pain in abdominal writhing responses induced by acetic acid. The present study also demonstrated that cardamonin produced significant analgesia in formalin-, capsaicin-, and glutamate-induced paw licking tests. In the thermal-induced nociception model, cardamonin exhibited significant increase in response latency time of animals subjected to hot-plate thermal stimuli. The rota-rod assessment confirmed that the antinociceptive activities elicited by cardamonin was not related to muscle relaxant or sedative effects of the compound. In conclusion, the present findings showed that cardamonin exerted significant peripheral and central antinociception through chemical- and thermal-induced nociception in mice through the involvement of TRPV1, glutamate, and opioid receptors.

Pain Perception and Side Effects During Saline Infusion Sonohysterography With a Balloon Catheter

2020 ◽  
Vol 39 (9) ◽  
pp. 1829-1837
Author(s):  
Firoozeh Ahmadi ◽  
Nadia Jahangiri ◽  
Fatemeh Zafarani ◽  
Ahmad Vosough
Keyword(s):  
Side Effects ◽  
Pain Perception ◽  
Balloon Catheter ◽  
Saline Infusion ◽  
Saline Infusion Sonohysterography

scholarly journals Discovery of Selective Cannabinoid CB2 Receptor Agonists by High-Throughput Screening

2017 ◽  
Vol 23 (4) ◽  
pp. 375-383 ◽  
Author(s):  
Lisa M. Ogawa ◽  
Neil T. Burford ◽  
Yu-Hsien Liao ◽  
Caitlin E. Scott ◽  
Ashley M. Hine ◽  
...  
Keyword(s):  
Side Effects ◽  
High Throughput ◽  
High Throughput Screening ◽  
Immune Modulation ◽  
Cannabinoid Receptors ◽  
Endocannabinoid System ◽  
Allosteric Modulators ◽  
Peripheral Tissues ◽  
Selective Agonists

The endocannabinoid system (ECS) plays a diverse role in human physiology ranging from the regulation of mood and appetite to immune modulation and the response to pain. Drug development that targets the cannabinoid receptors (CB1 and CB2) has been explored; however, success in the clinic has been limited by the psychoactive side effects associated with modulation of the neuronally expressed CB1 that are enriched in the CNS. CB2, however, are expressed in peripheral tissues, primarily in immune cells, and thus development of CB2-selective drugs holds the potential to modulate pain among other indications without eliciting anxiety and other undesirable side effects associated with CB1 activation. As part of a collaborative effort among industry and academic laboratories, we performed a high-throughput screen designed to discover selective agonists or positive allosteric modulators (PAMs) of CB2. Although no CB2 PAMs were identified, 167 CB2 agonists were discovered here, and further characterization of four select compounds revealed two with high selectivity for CB2 versus CB1. These results broaden drug discovery efforts aimed at the ECS and may lead to the development of novel therapies for immune modulation and pain management with improved side effect profiles.

Comparing cold and warm tumescent anesthesia for pain perception during and after the endovenous laser ablation procedure with 1470 nm diode laser

2013 ◽  
Vol 30 (1) ◽  
pp. 45-51 ◽  
Author(s):  
Mert Dumantepe ◽  
Ibrahim Uyar
Keyword(s):  
Laser Ablation ◽  
Side Effects ◽  
Room Temperature ◽  
Pain Perception ◽  
Visual Analog Score ◽  
Ablation Procedure ◽  
Endovenous Laser Ablation ◽  
Fluid Infiltration ◽  
Group A ◽  
Group B

Objective: The aim of this study was to compare the pain perception and side effects during and after endovenous laser ablation with a 1470 nm diode laser using cold or room temperature tumescence anesthesia. Methods: One hundred and one patients were randomly assigned in two groups. Group A received room temperature (+24℃) and Group B received cold (+4℃) tumescence fluid, which was used for local anesthesia in the track of great saphenous vein. A visual analog score was recorded immediately after the procedure. Patients were asked to register pain scores and the amount of pain medication consumed during the week. Results: There was no significant difference concerning gender, age, Clinical Etiological Anatomical Pathological Classification, body mass index, or diameter of the treated vein. In Group A, the mean linear endovenous energy density was 59.5 J/cm and in Group B, it was 60.4 J/cm. The average visual analog score after the endovenous laser ablation procedure in Group A was 5 and in Group B was 2. Third day after the procedure, the average visual analog score in Group A was 3 and in Group B was 1. Patients in Group B needed significantly less analgesics compared with patients in Group A ( p<0.05). The most frequent side effects in both groups were ecchymosis, induration, and minor paraesthesia, all of which were more common in Group A ( p < 0.001). Conclusions: To date, most published endovenous laser ablation series describe the use of room temperature tumescence fluid infiltration of the perivenous stroma for tumescent analgesia and protection against thermal injury to the nearby structures. We describe an alternative technique using cold tumescence fluid infiltration, which is equally effective as, but safer than, room temperature tumescence fluid infiltration, and which yields better visual analog scores.

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