The novel small molecule α9α10 nicotinic acetylcholine receptor antagonist ZZ-204G is analgesic

Chronic pain is inadequately managed with currently available classes of analgesic drugs. Recently, peptide antagonists of the alpha 9 alpha 10 nicotinic acetylcholine receptor were shown to be analgesic. The present study was conducted to characterize a novel small molecule, non-peptide antagonist at nicotinic receptors. The tetrakis-quaternary ammonium compound ZZ-204G was evaluated for functional activity on cloned nicotinic receptors expressed in Xenopus oocytes. In-vivo efficacy was assessed in rat models of tonic inflammatory pain (formalin test), neuropathic pain (chronic constriction nerve injury), and thermal nociception (tail flick test). ZZ-204G was an antagonist at nicotinic receptors inhibiting the alpha 9 alpha 10 subtype with an IC50 of 0.51 (0.35-0.72) nM. Antagonist activity at other nicotinic subtypes (alpha 1 beta 1 delta epsilon, alpha 2 beta 2, alpha 2 beta 4, alpha 3 beta 2, alpha 3 beta 4, alpha 4 beta 2, alpha 4 beta 4, alpha 6/alpha 3 beta 2 beta 3, alpha 6/alpha 3 beta 4 and alpha 7) was 10-1000-fold lower than at the alpha 9 alpha 10 subtype. In competition binding assays, the k(i) of ZZ-204G at gamma-aminobutyric acid(A), serotonin(3), gamma-aminobutyric acid(B), kappa- and mu-opioid receptors was 1000- to > 10,000-fold lower than at alpha 9 alpha 10 nicotinic receptors. Parenteral administration of ZZ-204G dose-dependently decreased nociceptive behaviors (paw flinches) in the formalin test and mechanical hyperalgesia in the chronic constriction nerve injury model of neuropathic pain. ZZ-204G was not antinociceptive in the tail flick assay. Results from the rotarod assay indicated that lower doses of ZZ-204G that were analgesic did not alter motor function. In summary, ZZ-204G represents a prototype small molecule antagonist for alpha 9 alpha 10 nicotinic receptors and provides a novel molecular scaffold for analgesic agents with the potential to treat chronic inflammatory or neuropathic pain. (C) 2011 Elsevier B.V. All rights reserved.