Identification of small molecule NPBWR1 agonists

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Principal Investigator: Ann M Decker
Organization: RESEARCH TRIANGLE INSTITUTE
Fiscal Year: 2024
Award: $120,166
Funding agency: National Institute on Drug Abuse

Abstract
Chronic pain is one of the leading health problems worldwide. Opioids have served as gold standard for
treating moderate to severe pain. However, opioids possess serious adverse effects that limit their use in
clinics. Therefore there is an unmet need for alternative effective and non-addictive pain treatments.
Neuropeptide B/W Receptor 1 (NPBWR1) has emerged as a novel pain target which upon activation can
produced analgesic effects on its own or in synergy with opioids. To date, all reported NPBWR1 agonists
are peptides or peptidomimetics that do not cross the blood brain barrier, requiring central administration.
To facilitate research on this promising target, we propose to perform a high throughput screen of our
diverse small molecule library to identify small molecule agonists (Aim 1). We have developed a battery of
in vitro functional assays to characterize NPBWR1 ligands including a cAMP, calcium mobilization and
TruPath assays. The 384-well cAMP assay has been demonstrated to have good robustness Z'>0.5, S/B >
20. Hits will be validated using counter screen and orthogonal assays. Validated hits will be assessed for
ADME profiling and selectivity against other targets (Aim 2). Completion of this proposal will yield small
molecule NPBWR1 that serve as starting points for subsequent medicinal chemistry optimization to develop
into therapeutics for chronic pain and other NPBWR1-mediated conditions.

Terms: <3'5'-cyclic ester of AMP><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adverse effects><Affect><Agonist><Analgesic Agents><Analgesic Drugs><Analgesic Preparation><Analgesics><Anodynes><Antinociceptive Agents><Antinociceptive Drugs><Assay><BBB permeabilization><BBB permeable><Bioassay><Bioavailability><Biological Assay><Biological Availability><Brain region><Carrageenan><Carrageenin><Cell Body><Cell Line><CellLine><Cells><Chemicals><Clinic><Closure by Ligation><Constipation><Cyclic AMP><DMSO><Demasorb><Demeso><Dependence><Diabetes Mellitus><Dimethyl Sulfoxide><Dimethylsulphinyl><Dimethylsulphoxide><Domoso><Dose><Dromisol><Drugs><Dryness><Ensure><Evaluation><Formalin><Formalin Tests><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G protein-coupled receptor 7><G-Protein-Coupled Receptors><GPCR><GPR7><Genes><Health><High Throughput Assay><Hyperalgesia><Hyperalgesic Sensations><Immune><Immunes><In Vitro><Inflammatory><Infumorph><Injections><KO mice><Kadian><Knock-out Mice><Knockout Mice><Laboratories><Libraries><Ligands><Ligation><Locus Coeruleus><MS Contin><MSir><Mediating><Medication><Medicinal Chemistry><Medulla Spinalis><Mesencephalic Central Gray><Metabolic><Midbrain Central Gray><Modeling><Morphia><Morphine><NIMH><NPBWR1><NPBWR1 gene><Naloxone><Narcan><Narcanti><National Institute of Mental Health><Nerve><Neuropathy><Neuropeptides><Nociception><Nucleus Pigmentosus Pontis><Null Mouse><Obesity><Opiate Receptors><Opiate agonist><Opiate receptor agonist><Opiates><Opioid><Opioid Receptor><Opioid agonist><Opioid receptor agonist><Oramorph><Oramorph SR><Pain><Pain Control><Pain Therapy><Pain management><Painful><Pathologic><Patients><Peptides><Periaqueductal Gray><Persons><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmaceutical Preparations><Physiologic Availability><Powder dose form><Powders><Property><Psychoactive Agents><Psychoactive Compound><Psychoactive Drugs><Psychopharmaceuticals><Psychotropic Drugs><Public Health><Regulation><Reporting><Research><Role><Roxanol><Sampling><Series><Solubility><Spinal Cord><Statex SR><Strains Cell Lines><Structure><System><Testing><Therapeutic><Validation><Vendor><addiction><addictive disorder><adenosine 3'5' monophosphate><adiposity><annulus of the aqueduct><blood-brain barrier permeabilization><blood-brain barrier permeable><bloodbrain barrier permeabilization><bloodbrain barrier permeable><blue nucleus><cAMP><calcium flux><calcium mobilization><chemical library><chronic constriction injury><chronic pain><chronic pain control><chronic pain intervention><chronic pain management><chronic pain therapy><chronic pain treatment><conditioned place preference><corpulence><counterscreen><cultured cell line><develop therapy><diabetes><drug candidate><drug discovery><drug/agent><effective therapy><effective treatment><high throughput screening><hyperalgia><inflammatory pain><intervention development><lead optimization><locus ceruleus structure><mechanical allodynia><midbrain central gray substance><neuropathic><neuropathic pain><neuropeptide B><neuropeptides B/W receptor 1><nociceptive><non-narcotic analgesic><non-opiate analgesic><non-opioid><non-opioid analgesic><non-opioid therapeutics><nonnarcotic analgesics><nonopiate analgesic><nonopioid><nonopioid analgesics><novel><pain killer><pain medication><pain model><pain reliever><pain treatment><painful neuropathy><painkiller><peptide mimetic><peptide mimic><peptidomimetics><periaqueductal gray matter><pharmacologic><place conditioning><programs><release of sequestered calcium ion into cytoplasm><response><scaffold><scaffolding><sciatic nerve><screening program><small molecule><small molecule libraries><social role><synergism><therapeutic candidate><therapy development><tool><treat chronic pain><treatment development><validations>