RTI-5152-12 explained

RTI-5152-12, or WW-12 (in patent), is a synthetic small-molecule agonist of the atypical chemokine receptor ACKR3 (CXCR7) that was derived from the naturally occurring alkaloid conolidine.[1] [2] [3] RTI-5152-12 has 15-fold improved potency towards ACKR3 relative to conolidine.

ACKR3 is a novel opioid receptor which functions as a broad-spectrum trap or scavenger for endogenous opioid peptides, including enkephalins, dynorphins, and nociceptin. The receptor acts as a negative modulator of the opioid system by decreasing the availability of opioid peptides for their classical receptors like the μ-opioid receptor.[4] Ligands of ACKR3, by competitively displacing endogenous opioid peptides from ACKR3, can potentiate the actions of these endogenous opioids and produce effects like analgesia and anxiolysis in animals.

RTI-5152-12 is being developed as a potential pharmaceutical drug and, as of December 2021, is in the preclinical stage of development for treatment of pain.[5] [6] [7] The chemical structure was not disclosed until a patent was published in June 2022.[8]

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Notes and References

  1. Palmer CB, Meyrath M, Canals M, Kostenis E, Chevigné A, Szpakowska M . Atypical opioid receptors: unconventional biology and therapeutic opportunities . Pharmacol Ther . 233 . 108014 . May 2022 . 34624426 . 10.1016/j.pharmthera.2021.108014 . Interestingly, ACKR3 has recently been demonstrated to be the main GPCR target of conolidine (Szpakowska et al., 2021), a natural analgesic alkaloid found in the bark of the tropical flowering shrub Tabernaemontana divaricate, which is used in traditional Chinese medicine to treat fever and pain (Tarselli et al., 2011). [...] Systematic chemical modifications of conolidine resulted in a analogue compound, RTI-5152-12, with 15-fold improved potency towards ACKR3. Notably, conolidine and RTI-5152-12 function similarly to LIH383 and conolidine's analgesic activity was proposed to rely on the inhibition of the scavenging functions of ACKR3 increasing the availability of analgesia-inducing endogenous opioid peptides for the classical ORs..
  2. Szpakowska M, Decker AM, Meyrath M, Palmer CB, Blough BE, Namjoshi OA, Chevigné A . The natural analgesic conolidine targets the newly identified opioid scavenger ACKR3/CXCR7 . Signal Transduct Target Ther . 6 . 1 . 209 . June 2021 . 34075018 . 8169647 . 10.1038/s41392-021-00548-w .
  3. WO . 2022136486A1 . Andy Chevigné, Martyna Szpakowska, Ojas Namjoshi, Bruce Edward Blough, Ann Marie Decker, Max Marc Roger Meyrath . Conolidine Analogues As Selective ACKR3 Modulators for the Treatment of Cancer and Cardiovascular Diseases . 30 June 2022 . 22 December 2021 . 22 December 2021 .
  4. Sowa JE, Tokarski K . Cellular, synaptic, and network effects of chemokines in the central nervous system and their implications to behavior . Pharmacol Rep . 73 . 6 . 1595–1625 . December 2021 . 34498203 . 8599319 . 10.1007/s43440-021-00323-2 . A recent elegant study has provided extensive evidence that ACKR3 is a chemokine receptor with the ability to bind opioid peptides; however, opioid binding did not trigger downstream signaling through this receptor [21]. Thus, it is suggested that ACKR3 serves scavenger functions for many opioids, especially enkephalins and dynorphins, by reducing their availability for their classical opioid receptors [21]. Accordingly, treatment with ACKR3 agonist LIH383, even at high concentration, did not produce any electrophysiological effect in PAG neurons, confirming the scavenging function of ACKR3 in this brain region..
  5. Web site: Straus . Mike . 2022 Pipeline Report: Capitalizing on Opportunity . Pharmaceutical Executive-12-01-2021 . MJH Life Sciences . 41 . 9 December 2021 . 9 August 2024 . Some of the other emerging pain management candidates in development include AT-121, ML-351, RTI-5152-12, and a Nav1.7 gene therapy. All of these potential therapies are in preclinical research..
  6. Web site: Jeong . Minseo . Chronic pain: Plant-derived compound may be new treatment . MedicalNewsToday . 9 June 2021 . 9 August 2024 . The scientists also extended their findings by chemically modifying conolidine to create a new compound, RTI-5152-12, which binds specifically to the ACKR3 receptor. In comparison with the natural conolidine, this synthetic compound showed increased binding to the ACKR3 receptor, making it a more effective potential treatment option. According to the LIH press release, the two research teams filed a joint patent application for RTI-5152-12 in December 2020. The study authors state: "Overall, the discovery of the potential mode of action of conolidine and its activity on ACKR3 is a significant step forward toward a more exhaustive understanding of its role in pain regulation, bearing great potential for novel drug development against chronic pain.".
  7. Web site: Natural Painkiller: New Research Advances the Treatment of Chronic Pain . SciTechDaily . 6 June 2021 . 9 August 2024 . The researchers also developed a synthetic analog of conolidine, RTI-5152-12, which displays an even greater activity on the receptor. [...] In parallel to characterizing the interaction between conolidine and ACKR3, the two teams went a step further. The scientists developed a modified variant of conolidine — which they called “RTI-5152-12” — which exclusively binds to ACKR3 with an even higher affinity. Like LIH383, a patented compound previously developed by Dr. Andy Chevigné and his team, RTI-5152-12 is postulated to increase the levels of opioid peptides that bind to classical opioid receptors in the brain, resulting in heightened painkilling activity. The LIH-RTI research teams established a collaboration agreement and filed a joint patent application in December 2020..
  8. PhD . Riemens . Rick . The discovery of small-molecule modulators for the ACKR3 receptor . Vrije Universiteit Amsterdam . 28 September 2023 . 10.5463/thesis.270 . 91 . In 2021, Szpakowska et al. disclosed conolidine and the chemically optimized RTI-5152-12 as opioid scavengers for ACKR3.45 The authors claimed that a patent application was filed; however, the patent is not publicly available yet (patent databases accessed on 23 05-2022)..

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