Description:
Abstract
USC researchers have identified two similar DOR-selective bitopic ligands that provide analgesia while minimizing seizure risk. These ligands, which target the conserved sodium site in DORs, have high affinity and potency for the DOR in G-protein pathways, but not arrestin pathways. In a mouse model, these ligands exhibited analgesic strength comparable to gabapentin without seizures, slowed respiration, or dysfunctional locomotion. With high bioavailability and brain penetration, this compound represents a strong preclinical candidate.
Benefit
- Analgesia without seizure, addiction, or respiration risk
- Targets G-protein but not arrestin pathways
- Highly bioavailable with good brain penetration
Market Application
The national opioid crisis has highlighted the need for effective analgesics with minimal side effects and low addiction potential. Mu opioid receptor agonists such as morphine are popular and effective analgesics, but they are associated with addiction, tolerance, and respiratory depression. Delta opioid receptor (DOR) agonists avoid these risks, but they do have a high potential to cause seizures, an on-target side effect and liability. A ligand that targets DOR G-protein pathways but not arrestin pathways may minimize seizure risk while operating as an effective, non-addictive analgesic.
Publications
Structure-guided design of partial agonists at an opioid receptor. Nat Commun. (2025).
Other
Stage of Development