Delving into the Latest Updates on D3 receptor antagonists/μ opioid receptor agonists(National Institutes of Health) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Compounds 84(National Institutes of Health)

Target

D3 receptor x μ opioid receptor

Action

antagonists, agonists

Mechanism

D3 receptor antagonists(Dopamine D3 receptor antagonists), μ opioid receptor agonists(Mu opioid receptor agonists)

Therapeutic Areas

Nervous System DiseasesOther Diseases

Active Indication

InflammationNeuralgia

Inactive Indication-

Originator Organization

National Institutes of Health

Active Organization

National Institutes of Health

Inactive Organization-

License Organization-

Drug Highest PhaseDiscovery

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC28H32N2O2

InChIKeyCRDDYQHSKSCCPP-LOSJGSFVSA-N

CAS Registry3033882-92-4

A new generation of dual-target μ opioid receptor (MOR) agonist/dopamine D₃ receptor (D₃R) 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 D₃R, respectively, improving the dopamine receptor subtype selectivity (e.g., D₃R over D₂R) and significantly enhancing central nervous system multiparameter optimization scores for predicted blood-brain barrier permeability. We identified the substituted trans-(2S,4R)-pyrrolidine and trans-phenylcyclopropyl amine as key dopaminergic moieties and tethered these to different opioid scaffolds, derived from the MOR agonists TRV130 (3) or loperamide (6). The lead compounds 46, 84, 114, and 121 have the potential of producing analgesic effects through MOR partial agonism with reduced opioid-misuse liability via D₃R antagonism. Moreover, the peripherally limited derivatives could have therapeutic indications for inflammation and neuropathic pain.

100 Deals associated with D3 receptor antagonists/μ opioid receptor agonists(National Institutes of Health)

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