Discovery of non-peptide, small molecule antagonists of α9α10 nicotinic acetylcholine receptors as novel analgesics for the treatment of neuropathic and tonic inflammatory pain

Abstract

A series of azaaromatic quaternary ammonium analogs has been discovered as potent and selective α9α10 nicotinic acetylcholine receptor (nAChR) antagonists. The preliminary structure-activity relationships of these analogs suggest that increased rigidity in the linker units results in higher potency in inhibition of α9α10 nAChRs and greater selectivity over α7 nAChRs. These analogs represent a new class of analgesic for the treatment of neuropathic and tonic inflammatory pain.

Cloning, synthesis, and characterization of αO-conotoxin GeXIVA, a potent α9α10 nicotinic acetylcholine receptor antagonist

“…The 4.6 nM IC 50 of GeXIVA [1,2] places it among the most potent peptides that target α9α10 nAChRs; the IC 50 s (nanomolar) for α-conotoxins Vc1.1, RgIA, and PeIA are 19, 5.2, and 6.9, respectively (43,46). Small-molecule antagonists of α9α10 nAChRs (which have IC 50 s as low as 0.51 nM) are also analgesic in rodent models of neuropathic pain (47)(48)(49), further validating α9α10 nAChR as an important therapeutic target. Each of these tested α9α10 antagonists produces long-lasting analgesia after single injection.…”

Conus Venom Peptide Pharmacology

“…It is noteworthy that these ␣9␣10-selective ␣-conotoxins are analgesic in different animal models of chronic pain, but there is an uncertainty about the true molecular target responsible for this effect. Indeed, whereas ␣9␣10 nAChR-selective small molecules were recently shown to also provide pain relief, N-type calcium channel inactivation through a novel interaction with GABA B receptor has also been proposed Zheng et al, 2011).…”

Novel small molecule alpha9 alpha10 nicotinic receptor antagonist prevents and reverses chemotherapy evoked neuropathic pain in rats

“…First, a dose of ZZ1-61c was based on maximum efficacy in a formalin model of persistent inflammatory pain. 18 Caution must be taken when comparisons are made between different pain models; a wide range of doses ought to be implemented in a further study. Second, since ZZ1-61c acts as antagonist at nAChRs 17,18 and has no efficacy on its own desensitization of receptors is less likely to occur.…”

“…18 ZZ1-1-61c was dissolved in saline and administered 100 µg/kg/day IP either along with or after completion of vincristine treatment.…”

“…[14][15][16] A number of these analogs also showed high affinity and selectivity for α9α10 nAChR expressed in Xenopus oocytes while they have significantly less potency on other subtypes. 17,18 These analogs demonstrated effectiveness against persistent inflammatory pain and posttraumatic neuropathy at doses well below those that produced motor dysfunction in rats. 17,19 However, they were not investigated in chemotherapy-evoked pain.…”