Inhibition of Inflammatory and Neuropathic Pain by Targeting a Mu Opioid Receptor/Chemokine Receptor5 Heteromer (MOR-CCR₅)

Abstract

Chemokine release promotes crosstalk between opioid and chemokine receptors that in part leads to reduced efficacy of morphine in the treatment of chronic pain. Based on the possibility that a MOR-CCR5 heteromer is involved in such crosstalk, we have synthesized bivalent ligands (MCC series) that contain mu opioid agonist and CCR5 antagonist pharmacophores linked through homologous spacers (14–24 atoms). When tested on lipopolysaccharide-inflamed mice, a member of the series (MCC22; 3e) with a 22-atom spacer exhibited profound antinociception (i.t. ED50 = 0.0146 pmol/mouse) that was >2000× greater than morphine. Moreover, MCC22 was ~3500× more potent than a mixture of mu agonist and CCR5 antagonist monovalent ligands. These data strongly suggest that MCC22 acts by bridging the protomers of a MOR-CCR5 heteromer having a TM5,6 interface. Molecular simulation studies are consistent with such bridging. This study supports the MOR-CCR5 heteromer as a novel target for treatment of chronic pain.

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

“…One difficulty in estimating the exact length is that the linkers are flexible and therefore nearly impossible to measure precisely. The estimated range for the optimal melanocortin linker is similar to that of other GPCR systems including the oxytocin (∼25 Å) [272], opioid (∼22 Å) [246, 273, 274], and dopamine receptors (∼25 Å) [247]. This provides strong evidence for a common design of bivalent ligands targeting GPCR systems and suggests this length may be the result of a common GPCR phenomenon (dimerization or high-order oligomerization).…”

Breaking barriers to novel analgesic drug development

“…For example, MDAN-21 (μ agonist/δ antagonist) 57–60 , a series of mu agonist/CB1 antagonist ligands 61 , MMG22 (μ agonist/mGluR5 antagonist) 62 and MCC22 (μ agonist/CCR5 antagonist) 63 have demonstrated potent antinociceptive activity in various preclinical rodent models of pain and are also devoid of tolerance or place preference, a measure of abuse liability. However, these molecules are rather large, raising questions about their bioavailability.…”

Altered expression of glial markers, chemokines, and opioid receptors in the spinal cord of type 2 diabetic monkeys

“…Following intrathecal administration, the CCR5 antagonist maraviroc not only attenuated development of neuropathic pain symptoms, but also increased morphine’s analgesic effects in rats [59]. As bivalent ligands with MOP agonist and CCR5 antagonist activities are being developed [60], it is crucial to assess the efficacy of such novel ligands in chronic pain states with varying etiologies. On the other hand, there is no change of NOP receptor expression in the SDH of diabetic monkeys (Figure 8).…”