Systematic Structure-Activity Relationship Study of Nalfurafine Analogues toward Development of Potentially Nonaddictive Pain Management Treatments.

Despite the availability of numerous pain medications, the current array of Food and Drug Administration-approved options falls short in adequately addressing pain states for numerous patients and consequently worsens the opioid crisis. Thus, it is imperative for basic research to develop novel and nonaddictive pain medications. Toward addressing this clinical goal, nalfurafine (NLF) was chosen as a lead and its structure-activity relationship (SAR) systematically studied through design, syntheses, and in vivo characterization of 24 analogues. Two analogues, 21 and 23, showed longer durations of action than NLF in a warm-water tail immersion assay, produced in vivo effects primarily mediated by KOR and DOR, penetrated the blood-brain barrier, and did not function as reinforcers. Additionally, 21 produced fewer sedative effects than NLF. Taken together, these results aid the understanding of NLF SAR and provide insights for future endeavors in developing novel nonaddictive therapeutics to treat pain.

Nor-LAAM loaded PLGA Microparticles for Treating Opioid Use Disorder.

The treatment landscape for opioid use disorder (OUD) faces challenges stemming from the limited efficacy of existing medications, poor adherence to prescribed regimens, and a heightened risk of fatal overdose post-treatment cessation. Therefore, there is a pressing need for innovative therapeutic strategies that enhance the effectiveness of interventions and the overall well-being of individuals with OUD. This study explored the therapeutic potential of nor-Levo-α-acetylmethadol (nor-LAAM) to treat OUD. We developed sustained release nor-LAAM-loaded poly (lactic-co-glycolic acid) (PLGA) microparticles (MP) using a hydrophobic ion pairing (HIP) approach. The nor-LAAM-MP prepared using HIP with pamoic acid had high drug loading and exhibited minimal initial burst release and sustained release. The nor-LAAM-MP was further optimized for desirable particle size, drug loading, and release kinetics. The lead nor-LAAM-MP (F4) had a relatively high drug loading (11 wt.%) and an average diameter (19 µm) and maintained a sustained drug release for 4 weeks. A single subcutaneous injection of nor-LAAM-MP (F4) provided detectable nor-LAAM levels in rabbit plasma for at least 15 days. We further evaluated the therapeutic efficacy of nor-LAAM-MP (F4) in a well-established fentanyl-addiction rat model, and revealed a marked reduction in fentanyl choice and withdrawal symptoms in fentanyl-dependent rats. These findings provide insights into further developing long-acting nor-LAAM-MP for treating OUD. It has the potential to offer a new effective medication to the existing sparse armamentarium of products available to treat OUD.

Characterization of a Potential KOR/DOR Dual Agonist with No Apparent Abuse Liability via a Complementary Structure-Activity Relationship Study on Nalfurafine Analogues.

Discovery of analgesics void of abuse liability is critical to battle the opioid crisis in the United States. Among many strategies to achieve this goal, targeting more than one opioid receptor seems promising to minimize this unwanted side effect while achieving a reasonable therapeutic profile. In the process of understanding the structure-activity relationship of nalfurafine, we identified a potential analgesic agent, NMF, as a dual kappa opioid receptor/delta opioid receptor agonist with minimum abuse liability. Further characterizations, including primary in vitro ADMET studies (hERG toxicity, plasma protein binding, permeability, and hepatic metabolism), and in vivo pharmacodynamic and toxicity profiling (time course, abuse liability, tolerance, withdrawal, respiratory depression, body weight, and locomotor activity) further confirmed NMF as a promising drug candidate for future development.