LIH383

LIH383 is an octapeptide and highly potent and selective agonist of the atypical chemokine receptor ACKR3 (CXCR7) that was derived from the opioid peptide adrenorphin.^[1]^[2]^[3]^[4]^[5] ACKR3 is a novel opioid receptor which functions as a broad-spectrum trap or scavenger for endogenous opioid peptides, including enkephalins, dynorphins, and nociceptin, and thereby acts as a negative modulator of the opioid system.^[3]^[4] By displacing them from ACKR3 and thereby increasing their availability, LIH383 potentiates the actions of endogenous opioids, for instance their analgesic effects.^[1]^[3]^[4]^[6] Other ligands of ACKR3 include conolidine, CCX771, RTI-5152-12, and VUF15485.^[1]^[6]^[7]

Other namesLIH-383; FGGFMRRK-NH₂; L-Phenylalanylglycylglycyl-L-phenylalanyl-L-methionyl-N⁵-(diaminomethylene)-L-ornithyl-N⁵-(diaminomethylene)-L-ornithyl-L-lysine

CAS Number

2866266-58-0

PubChem CID

168287525

ChemSpider

129306945

Quick facts Clinical data, Other names ...

LIH383
Clinical data

Other names	LIH-383; FGGFMRRK-NH₂; L-Phenylalanylglycylglycyl-L-phenylalanyl-L-methionyl-N⁵-(diaminomethylene)-L-ornithyl-N⁵-(diaminomethylene)-L-ornithyl-L-lysine
Identifiers
IUPAC name (2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[2-[[(2S)-2-amino-3-phenylpropanoyl]amino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]hexanamide
CAS Number	2866266-58-0
PubChem CID	168287525
ChemSpider	129306945
ChEMBL	ChEMBL5194677
Chemical and physical data
Formula	C₄₅H₇₂N₁₆O₈S
Molar mass	997.24 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES CSCC[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(=O)N)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CNC(=O)CNC(=O)[C@H](CC2=CC=CC=C2)N
InChI InChI=1S/C45H72N16O8S/c1-70-23-19-34(61-43(69)35(25-29-14-6-3-7-15-29)57-37(63)27-55-36(62)26-56-39(65)30(47)24-28-12-4-2-5-13-28)42(68)60-33(18-11-22-54-45(51)52)41(67)59-32(17-10-21-53-44(49)50)40(66)58-31(38(48)64)16-8-9-20-46/h2-7,12-15,30-35H,8-11,16-27,46-47H2,1H3,(H2,48,64)(H,55,62)(H,56,65)(H,57,63)(H,58,66)(H,59,67)(H,60,68)(H,61,69)(H4,49,50,53)(H4,51,52,54)/t30-,31-,32-,33-,34-,35-/m0/s1 Key:HKVZPBVWPFDBBQ-LBBUGJAGSA-N

References

[1]
Palmer CB, Meyrath M, Canals M, Kostenis E, Chevigné A, Szpakowska M (May 2022). "Atypical opioid receptors: unconventional biology and therapeutic opportunities". Pharmacology & Therapeutics. 233 108014. doi:10.1016/j.pharmthera.2021.108014. PMID 34624426. This is reinforced by the finding that blocking ACKR3 scavenging through administration of the modulator LIH383 leads to potentiation of dynorphin A effects on the classical opioid receptors, i.e. an increase in the inhibition of neuronal firing (Meyrath et al., 2020). Additionally, ACKR3 was recently shown to bind the natural analgesic molecule conolidine, further pointing to the involvement of this receptor in pain (Szpakowska et al., 2021). [...] Indeed, targeting ACKR3 with the highly specific small-molecule compound CCX771 was described to have, synergistically with ACTH, an anxiolytic-like effect on behavior in mice (Ikeda et al., 2013). Moreover, the effect of adrenorphin-derived small peptide LIH383, which blocks ACKR3 scavenging function, was recently addressed in an ex vivo rat locus coeruleus model where it potentiates the effect of endogenous opioids (Meyrath et al., 2020). [...] Systematic chemical modifications of conolidine resulted in an 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]
Sjöberg E, Meyrath M, Chevigné A, Östman A, Augsten M, Szpakowska M (2020). "The diverse and complex roles of atypical chemokine receptors in cancer: From molecular biology to clinical relevance and therapy". Advances in Cancer Research. Vol. 145. Elsevier. pp. 99–138. doi:10.1016/bs.acr.2019.12.001. ISBN 978-0-12-820230-2. PMID 32089166. Recently, LIH383, an octapeptide derived from an endogenous ACKR3 ligand, was also reported as a subnanomolar agonist of the receptor.
[3]
Sowa JE, Tokarski K (December 2021). "Cellular, synaptic, and network effects of chemokines in the central nervous system and their implications to behavior". Pharmacological Reports. 73 (6): 1595–1625. doi:10.1007/s43440-021-00323-2. PMC 8599319. PMID 34498203. 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.
[4]
"Could This Opioid Scavenger Avert a Crisis?". Neuroscience from Technology Networks. 22 June 2020. Retrieved 9 August 2024.
[5]
Meyrath M, Szpakowska M, Zeiner J, Massotte L, Merz MP, Benkel T, et al. (June 2020). "The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides". Nature Communications. 11 (1): 3033. Bibcode:2020NatCo..11.3033M. doi:10.1038/s41467-020-16664-0. PMC 7305236. PMID 32561830.
[6]
Szpakowska M, Decker AM, Meyrath M, Palmer CB, Blough BE, Namjoshi OA, et al. (June 2021). "The natural analgesic conolidine targets the newly identified opioid scavenger ACKR3/CXCR7". Signal Transduction and Targeted Therapy. 6 (1): 209. doi:10.1038/s41392-021-00548-w. PMC 8169647. PMID 34075018.
[7]
Zarca AM, Adlere I, Viciano CP, Arimont-Segura M, Meyrath M, Simon IA, et al. (March 2024). "Pharmacological Characterization and Radiolabeling of VUF15485, a High-Affinity Small-Molecule Agonist for the Atypical Chemokine Receptor ACKR3". Molecular Pharmacology. 105 (4): 301–312. doi:10.1124/molpharm.123.000835. hdl:1871.1/e4f88deb-01a7-44e3-acae-01f60da586f8. PMID 38346795.

References

External links

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