A mu opioid receptor superagonist that produces analgesia with minimal adverse effects

ABSTRACT: Developing safe and effective pain medications is an ongoing challenge for human health. Mu opioid receptor (MOR) agonists are essential pain medications, but their high intrinsic efficacy induces adverse side effects, including respiratory depression, constipation, tolerance, dependence, withdrawal, and addiction. Strategies to limit such effects traditionally include developing MOR agonists that have low intrinsic efficacy or preferentially activate G protein over β-arrestin signaling. We report the discovery of a novel MOR superagonist with supraphysiological intrinsic efficacy and a unique pharmacological profile that produces effective analgesia in rodents with minimal adverse side effects. N-desethyl-fluornitrazene (DFNZ) was derived from a class of synthetic benzimidazole opioids called Nitazenes. DFNZ has a unique spatiotemporal MOR cellular signaling profile that favors G protein activation over β-arrestin recruitment, impaired brain penetrance, and diminished efficacy at the MOR-galanin 1 receptor (Gal1R) heteromer. DFNZ does not induce respiratory depression, tolerance, or MOR desensitization after repeated exposure. Compared to other MOR agonists, DFNZ does not increase dopamine transmission in nucleus accumbens and has weaker reinforcing effects in the drug self-administration procedure. These results provide novel insights on MOR pharmacology, have important implications for pain and addiction treatment, and challenge the prevailing dogma that MOR superagonists cannot constitute safe and effective therapeutics.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hek-293t Cell

SUBMITTER: Dain Brademan  

LAB HEAD: Ruth Huttenhain, PhD

PROVIDER: PXD062863 | Pride | 2026-05-25

REPOSITORIES: Pride