View source for RTI-5152-12

{{Short description|Synthetic opioid modulator}}
{{Drugbox
| Verifiedfields =
| Watchedfields =
| verifiedrevid =
| image = RTI-5152-12.png
| width =
<!-- Clinical data -->
| tradename =
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category =
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA =
| legal_UK =
| legal_US =
| legal_status =
| routes_of_administration =
| class = [[ACKR3]] (CXCR7) [[agonist]]; [[Opioid modulator]]
<!-- Pharmacokinetic data -->
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life =
| excretion =
<!-- Identifiers -->
| CAS_number_Ref =
| CAS_number =
| CAS_supplemental =
| ATC_prefix =
| ATC_suffix =
| ATC_supplemental =
| PubChem = 155927823
| IUPHAR_ligand =
| DrugBank_Ref =
| DrugBank =
| ChemSpiderID_Ref =
| ChemSpiderID =
| UNII =
| KEGG =
| ChEBI =
| ChEMBL =
| synonyms = WW-12 (patent)<ref name="WO2022136486A1" />
<!-- Chemical data -->
| IUPAC_name = [(3''E'',4''R'')-3-ethylidene-1-pentylpiperidin-4-yl]-(1''H''-indol-2-yl)methanone
| C=21 | H=28 | N=2 | O=1
| SMILES = CCCCCN1CC[C@H](/C(=C\C)/C1)C(=O)C2=CC3=CC=CC=C3N2
| StdInChI_Ref =
| StdInChI = 1S/C21H28N2O/c1-3-5-8-12-23-13-11-18(16(4-2)15-23)21(24)20-14-17-9-6-7-10-19(17)22-20/h4,6-7,9-10,14,18,22H,3,5,8,11-13,15H2,1-2H3/b16-4-/t18-/m1/s1
| StdInChIKey_Ref =
| StdInChIKey = MUZOMTWDNLINCG-QBSXKKPKSA-N
}}
'''RTI-5152-12''', or '''WW-12''' (in [[patent]]), is a [[synthetic compound|synthetic]] [[small molecule|small-molecule]] [[agonist]] of the [[chemokine receptor|atypical chemokine receptor]] [[ACKR3]] (CXCR7) that was [[chemical derivative|derived]] from the [[natural product|naturally occurring]] [[alkaloid]] [[conolidine]].<ref name="PalmerMeyrathCanals2022">{{cite journal | vauthors = Palmer CB, Meyrath M, Canals M, Kostenis E, Chevigné A, Szpakowska M | title = Atypical opioid receptors: unconventional biology and therapeutic opportunities | journal = Pharmacol Ther | volume = 233 | issue = | pages = 108014 | date = May 2022 | pmid = 34624426 | doi = 10.1016/j.pharmthera.2021.108014 | url = | quote = 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.}}</ref><ref name="SzpakowskaDeckerMeyrath2021">{{cite journal | vauthors = Szpakowska M, Decker AM, Meyrath M, Palmer CB, Blough BE, Namjoshi OA, Chevigné A | title = The natural analgesic conolidine targets the newly identified opioid scavenger ACKR3/CXCR7 | journal = Signal Transduct Target Ther | volume = 6 | issue = 1 | pages = 209 | date = June 2021 | pmid = 34075018 | pmc = 8169647 | doi = 10.1038/s41392-021-00548-w | url = }}</ref><ref name="SciTechDaily2021" /><ref name="WO2022136486A1">{{cite patent | country=WO | number=2022136486A1 | inventor=Andy Chevigné, Martyna Szpakowska, Ojas Namjoshi, Bruce Edward Blough, Ann Marie Decker, Max Marc Roger Meyrath | status= | title=Conolidine Analogues As Selective ACKR3 Modulators for the Treatment of Cancer and Cardiovascular Diseases | pubdate=30 June 2022 | gdate= | fdate=22 December 2021 | pridate=22 December 2021 | assign1= | assign2= | url=https://patents.google.com/patent/WO2022136486A1/en}}</ref> RTI-5152-12 has 15-fold improved [[potency (pharmacology)|potency]] towards ACKR3 relative to conolidine.<ref name="PalmerMeyrathCanals2022" /><ref name="SzpakowskaDeckerMeyrath2021" /><ref name="WO2022136486A1" />
ACKR3 is a novel [[opioid receptor]] which functions as a broad-spectrum [[scavenger receptor (endocrinology)|trap or scavenger]] for [[endogenous]] opioid peptides, including [[enkephalin]]s, [[dynorphin]]s, and [[nociceptin]].<ref name="PalmerMeyrathCanals2022" /><ref name="SowaTokarski2021" /> The receptor acts as a negative modulator of the [[opioid|opioid system]] by decreasing the availability of opioid peptides for their classical receptors like the [[μ-opioid receptor]].<ref name="PalmerMeyrathCanals2022" /><ref name="SowaTokarski2021">{{cite journal | vauthors = Sowa JE, Tokarski K | title = Cellular, synaptic, and network effects of chemokines in the central nervous system and their implications to behavior | journal = Pharmacol Rep | volume = 73 | issue = 6 | pages = 1595–1625 | date = December 2021 | pmid = 34498203 | pmc = 8599319 | doi = 10.1007/s43440-021-00323-2 | url = | quote = 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.}}</ref> [[Ligand (biochemistry)|Ligand]]s 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.<ref name="PalmerMeyrathCanals2022" /><ref name="SzpakowskaDeckerMeyrath2021" />
RTI-5152-12 is [[drug development|being developed]] as a potential [[pharmaceutical drug]] and, as of December 2021, is in the [[preclinical research|preclinical]] stage of development for treatment of [[pain]].<ref name="Straus2021">{{cite web | last=Straus | first=Mike | title=2022 Pipeline Report: Capitalizing on Opportunity | series=Pharmaceutical Executive-12-01-2021 | publisher=MJH Life Sciences | volume=41 | date=9 December 2021 | url=https://www.pharmexec.com/view/2022-pipeline-report-capitalizing-on-opportunity | access-date=9 August 2024 | quote = 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.}}</ref><ref name="Jeong2021">{{cite web | last=Jeong | first=Minseo | title=Chronic pain: Plant-derived compound may be new treatment | website=MedicalNewsToday | date=9 June 2021 | url=https://www.medicalnewstoday.com/articles/plant-derived-compound-may-help-treat-chronic-pain#An-exciting-new-treatment-avenue | access-date=9 August 2024 | quote = 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."}}</ref><ref name="SciTechDaily2021">{{cite web | title=Natural Painkiller: New Research Advances the Treatment of Chronic Pain | website=SciTechDaily | date=6 June 2021 | url=https://scitechdaily.com/natural-painkiller-new-research-advances-the-treatment-of-chronic-pain/ | access-date=9 August 2024 | quote = 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.}}</ref> The [[chemical structure]] was not disclosed until a patent was published in June 2022.<ref name="Riemens2023">{{cite thesis | degree=PhD | last=Riemens | first=Rick | title=The discovery of small-molecule modulators for the ACKR3 receptor | publisher=Vrije Universiteit Amsterdam | date=28 September 2023 | doi=10.5463/thesis.270 | page=91 | url=https://research.vu.nl/ws/portalfiles/portal/260792999/20230712+phd+thesis+changed+embargo+version+-+64c0fdf8dd97f.pdf#page=91 | quote = 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).}}</ref><ref name="SzpakowskaDeckerMeyrath2021" />
==See also==
* [[LIH383]]
==References==
{{Reflist}}
==External links==
* [https://www.hedweb.com/gooddrug.htm#:~:text=CONOLIDINE%20/%20RTI%2D5152%2D12 The Good Drug Guide - Conolidine / RTI-5152-12 - David Pearce]
{{Chemokine receptor modulators}}
{{Opioid receptor modulators}}
[[Category:Opioid modulators]]
[[Category:Opioid peptides]]
[[Category:Piperidines]]
[[Category:Indoles]]
[[Category:Ketones]]