Pentameric Ligand-Gated Ion Channels as Pharmacological Targets Against Chronic Pain

Abstract

Chronic pain is a common detrimental condition that affects around 20% of the world population. The current drugs to treat chronic pain states, especially neuropathic pain, have a limited clinical efficiency and present significant adverse effects that complicates their regular use. Recent studies have proposed new therapeutic strategies focused on the pharmacological modulation of G-protein-coupled receptors, transporters, enzymes, and ion channels expressed on the nociceptive pathways. The present work intends to summarize recent advances on the pharmacological modulation of pentameric ligand-gated ion channels, which plays a key role in pain processing. Experimental data have shown that novel allosteric modulators targeting the excitatory nicotinic acetylcholine receptor, as well as the inhibitory GABA_A and glycine receptors, reverse chronic pain-related behaviors in preclinical assays. Collectively, these evidences strongly suggest the pharmacological modulation of pentameric ligand-gated ion channels is a promising strategy towards the development of novel therapeutics to treat chronic pain states in humans.

Keywords: preclinical research; allosteric modulation; analgesia; chronic pain; drug development; pentameric ligand-gated ion channels.

Figure 1

Binding sites of analgesic compounds on pLGIC structures. Top: The purple structure represent the 5-HT3R (PDB:6HIQ). The black square highlight the tropeine binding site described within the orthosteric site (blue). The green structure represents nAChRs (PDB: 4AQ9). The black squares show two different binding sites for analgesic molecules (ECD and TMD). The binding site within the ECD correspond to the orthosteric binding site. The inset show chemical compounds and toxins-derivate peptides that may interact with residues on the orthosteric site (red). Conversely, the PAM PNU-120596 binds to an intra-subunit cavity in the TMD (yellow). Bottom: The cyan structure represents GABA_ARs (PDB: 6HUO). The black square shows the binding site of BDZ at the ECD, in the interphase between α and γ subunits. The yellow structure represent GlyRs (PDB: 5TIO). The black squares show three putative binding sites for analgesic compounds. The tricyclic sulfonamides AM-1488 and AM-3607 binds to ECD, in the interphase between two adjacent α subunits. The binding site for DH-CBD has been described within the TMD. The compound 2,6-DTBP has been proposed to interact with α3GlyRs in an ICD a putative binding site.