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Principal Investigator: Susruta Majumdar
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $601,979
Funding agency: National Institute on Drug Abuse
ABSTRACT
Opioids until recently were the drugs of choice to treat moderate to severe chronic pain. Decades of intensive
research has led to the pharmacological characterization of countless synthetic and semi-synthetic opioid
derivatives. However, an ideal compound, devoid of serious side-effects such as respiratory depression,
dependence, and addiction, has not yet been identified. Opioid activation of mu opioid receptor (MOR) G protein
signaling pathways is believed to cause both desirable analgesia as well as undesirable adverse effects like
respiratory depression. Since MOR can couple with six Gi/o/z subtypes, namely Gi1, Gi2, Gi3, GOA, GOB and Gz, we
hypothesize that it may be possible to achieve functional selectivity by activating an individual Gα-isoform and/or
a combination of these isoforms. Our preliminary data shows that bitopics of fentanyl show unique Gi/o/z signaling
as well as a behavioral profile distinct from typical opioids. To this end, we have also obtained cryoEM structures
of MOR bound to one lead bitopics, C6 guano (3.3Å), and an analog of C6 guano named LG94 (3.4Å) getting
insights into distinct modes of ligand binding that also involves engagement of an allosteric binding site. We have
identified two distinct modes of engaging the sodium binding allosteric site in MOR and identified an antagonist
as well. In this study, we will interrogate Gα-subtype bias through screening of additional analogs, across both
fentanyl and morphinan based templates as well as novel indole-based templates and targeting the allosteric
site with additional bitopics with higher potency and optimal drug like properties. We will also develop a first in
class antagonist on the fentanyl template. High resolution cryoEM will be used on promising analogs to enable
structure-function studies and ligand binding fine-tuning. This, in turn, will enable us to design analogs that are
more effective and possibly display a more advantageous side-effect profile (no respiratory depression while
showing analgesia) than their parent compounds. These probes will also allow us to build a better framework for
understanding MOR Gα-subtype signaling and facilitate identification of useful preclinical candidates for the
treatment of pain/OUD in the near future. Furthermore, any novel antagonists could become tools in fighting
opioid-related substance abuse.
Terms: <3'5'-cyclic ester of AMP><Absence of pain sensation><Absence of sensibility to pain><Actiq><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adverse effects><Allosteric Site><American><Analgesic Agents><Analgesic Drugs><Analgesic Preparation><Analgesics><Animals><Anodynes><Antinociceptive Agents><Antinociceptive Drugs><Arrestins><Assay><Attenuated><Behavioral><Binding><Binding Sites><Bioassay><Biological Assay><Brain><Brain Nervous System><Cell Communication and Signaling><Cell Signaling><Charge><Chemicals><Chemistry><Clinical><Collaborations><Combining Site><Coupled><Cryo-electron Microscopy><Cryoelectron Microscopy><Cyclic AMP><Data><Dependence><Development><Drug Therapy><Drugs><Duragesic><Electron Cryomicroscopy><Encephalon><Epidemic><Feels no pain><Fentanest><Fentanyl><Fentyl><Future><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein Signaling Pathway><G-Protein-Coupled Receptors><G-Proteins><GPCR><GTP-Binding Proteins><GTP-Regulatory Proteins><Generations><Goals><Guanidines><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Regulatory Proteins><Individual><Indoles><Infumorph><Intracellular Communication and Signaling><Isoforms><Kadian><Laboratories><Lead><Length of Life><Ligand Binding><Ligands><Longevity><MS Contin><MSir><Maps><Medication><Metabolic><Mice><Mice Mammals><Modification><Molecular Interaction><Morphia><Morphinans><Morphine><Murine><Mus><Na element><Naloxone><Names><Narcan><Narcanti><No sensitivity to pain><Opiate agonist><Opiate receptor agonist><Opiates><Opioid><Opioid Analgesics><Opioid Receptor Binding><Opioid agonist><Opioid receptor agonist><Oramorph><Oramorph SR><Overdose><Pain><Pain Control><Pain Therapy><Pain management><Painful><Parents><Patients><Pb element><Penetration><Pharmaceutical Preparations><Pharmacology><Pharmacotherapy><Phentanyl><Physical Dependence><Physiology><Property><Protein Family><Protein Isoforms><Reactive Site><Receptor Protein><Reporting><Research><Resolution><Respiratory Depression><Retinal S-Antigen><Role><Roxanol><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Pathway from G-Protein Families><Signaling Protein><Site><Sodium><Statex SR><Structure><Substance abuse problem><Testing><Ventilatory Depression><Withdrawal><abuse of substances><addiction><addictive disorder><adenosine 3'5' monophosphate><analgesia><analog><antagonism><antagonist><antinociception><antinociceptive><attenuate><attenuates><biological signal transduction><cAMP><chronic pain><comparable efficacy><comparative efficacy><compare efficacy><conditioned place preference><cryo-EM><cryoEM><cryogenic electron microscopy><depressed breathing><depression of breathing><design><designing><developmental><drug treatment><drug/agent><fighting><heavy metal Pb><heavy metal lead><improved><in vivo><insight><licit opioid><mouse model><mu opioid receptors><murine model><name><named><naming><novel><opiate analgesia><opiate analgesic><opiate crisis><opiate medication><opiate pain medication><opiate pain reliever><opiate use disorder><opioid analgesia><opioid anesthetic><opioid crisis><opioid epidemic><opioid medication><opioid pain medication><opioid pain reliever><opioid painkiller><opioid use disorder><pain killer><pain medication><pain relief><pain reliever><pain treatment><painkiller><parent><pharmacologic><place conditioning><pre-clinical><preclinical><prescribed opiate><prescribed opioid><prescription opiate><prescription opioid><receptor><receptor function><recruit><relieve pain><resolutions><screening><screenings><side effect><social role><structural biology><substance abuse><synthetic opiate><synthetic opioid><tool><μ opioid receptors><μ-OR><μOR>