Bivalent ligand that activates mu opioid receptor and antagonizes mGluR5 receptor reduces neuropathic pain in mice

Abstract

The mu opioid receptor (MOR) and metabotropic glutamate receptor 5 (mGluR5) are well-established pharmacological targets in the management of chronic pain. Both receptors are expressed in spinal cord. MMG22, a bivalent ligand containing two pharmacophores separated by 22 atoms that simultaneously activates MOR and antagonizes mGluR5 has been shown to produce potent reversal of tactile hypersensitivity in rodent models of LPS- and bone-cancer-induced chronic pain. The present study assessed whether intrathecal MMG22 also is effective in reducing pain of neuropathic origin. Further, we theorized that MMG22 should reduce hyperalgesia in nerve-injured mice in a manner consistent with a synergistic interaction between MOR and mGluR5. Several weeks following spared nerve injury, tactile hypersensitivity was reversed in mice by intrathecal injection of MMG22 (0.01–10 nmol) but also by its shorter spacer analog, MMG10, with similar potency. The potencies of the bivalent ligands were 10-14-fold higher than those of the compounds upon which the bivalent structure was based, the MOR agonist oxymorphone and the mGluR5 antagonist MPEP. Co-administration of oxymorphone and MPEP demonstrated analgesic synergism, an interaction confirmed by isobolographic analysis. The present study indicates that in the spared nerve-injury induced model of neuropathic pain, the two pharmacophores of the bivalent ligands MMG22 and MMG10 target MOR and mGluR5 as separate receptor monomers. The observed increase in potency of MMG22 and MMG10, compared to oxymorphone and MPEP, may reflect the synergistic interaction of the two pharmacophores of the bivalent ligand acting at their respective separate receptor monomers.

Advances in Achieving Opioid Analgesia Without Side Effects

“…The former was designed to target μ–mGluR5 heteromers, as it consists of μ-agonist (oxymorphamine) and mGluR5 antagonist (metoxy-2-methyl-6-(phenylethynyl)-pyridine) connected by a 22-atom spacer. Compared to morphine or the individual pharmacophores, MMG22 was more potent, but similarly efficacious in mouse models of inflammatory, bone cancer ( Akgün et al, 2013 ), and neuropathic pain ( Peterson et al, 2017 ). However, as the latter study showed that MMG22 acted at μ-receptors and mGluR5 as separate monomers rather than heteromers ( Peterson et al, 2017 ), and the examination of side effects was very limited ( Akgün et al, 2013 ), a rigorous evaluation of a broad adverse effect spectrum will be essential to justify the utility of this compound.…”

The Endocannabinoid System as a Target in Cancer Diseases: Are We There Yet?

“…Therefore, the accomplishment of at least two out of three criteria is required for the acceptance of a GPCR heteromer (Jonas and Hanyaloglu, 2017). The main strategies to target GPCR heteromers are the generation of selective compounds, which exhibit higher efficacy in tissues from wild type animals or in cells expressing both receptors than in knock-out animals tissues or in cell only expressing the individual receptors (Akgün et al, 2013; Gomes et al, 2013a; Molero et al, 2015; Nimczick and Decker, 2015; Peterson et al, 2017). Likewise, the use of membrane-permeable peptides that target the dimerization interface or heteromer-selective antibodies that can recognize an epitope in the heteromer but not in the individual protomers, have been most useful to detect GPCRs heteromers in vivo (Gupta et al, 2010; He et al, 2011; Viñals et al, 2015; Gomes et al, 2016a; Moreno et al, 2017; Jacobs et al, 2018).…”

μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation

“…The results were analyzed by nonlinear curve fitting of the inhibition curves of the compounds utilizing the Graph-Pad Prism program. 4,6 Hill slope coefficients were fixed to unity during the calculation.…”

“…The main tools in these have been numerous homo and heterobivalent ligands, designed as specific pharmacological probes. Some of the representative heterodimers include ΜOR/DOR, 2 ΜOR/ΚOR, 4 ΜOR/cannabinoid receptor type 1, 5 ΜOR/metabotropic glutamate receptor type 5, 6 ΜOR/chemokine-receptor type 5, 7 ΜOR/NSAIDs 8 and ΜOR/N-type Ca 2+ channels. 9 It is known that opioid and dopamine receptors are co-distributed in many brain tissues, indicating possible functional interaction.…”