LIH383 is a highly selective agonist of the atypical chemokine receptor, ACKR3 (formerly known as CXCR7). Functionally, ACKR3 is a scavenger receptor for a wide variety of opioid peptides, especially enkephalins and dynorphins, reducing their availability for the classical opioid receptors. LIH383 competes directly with CXCL12-AF647 for ACKR3 binding at low nanomolar concentrations and is more potent in inducing beta-arrestin recruitment to ACKR3 than the full-length chemokine ligands CXCL12 and CXCL11, with EC50 values of 1.2 nM and 2.2 nM respectively, and no effect on of any other opioid or chemokine receptor at concentrations up to 3µM. LIH383 can restrain the negative regulatory function of ACKR3 on opioid peptides and potentiate their activity in rat brain.
