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

Joseph R. Holtman, Linda P. Dwoskin, Cheryl Dowell, Elzbieta P. Wala, Zhenfa Zhang, Peter A. Crooks, J. Michael McIntosh

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Chronic pain is inadequately managed with currently available classes of analgesic drugs. Recently, peptide antagonists of the α9α10 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 α9α10 subtype with an IC 50 of 0.51 (0.35-0.72) nM. Antagonist activity at other nicotinic subtypes (α1β1δε, α2β2, α2β4, α3β2, α3β4, α4β2, α4β4, α6/α3β2β3, α6/α3β4 and α7) was 10-1000-fold lower than at the α9α10 subtype. In competition binding assays, the k i of ZZ-204G at γ-aminobutyric acid(A), serotonin(3), γ-aminobutyric acid(B), κ- and μ-opioid receptors was 1000- to > 10,000-fold lower than at α9α10 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 α9α10 nicotinic receptors and provides a novel molecular scaffold for analgesic agents with the potential to treat chronic inflammatory or neuropathic pain.

Original languageEnglish
Pages (from-to)500-508
Number of pages9
JournalEuropean Journal of Pharmacology
Volume670
Issue number2-3
DOIs
StatePublished - Nov 30 2011

Bibliographical note

Funding Information:
This work was supported by U19 DA017548, NIH MH53631, GM48677 and a seed grant from the University of Utah Research Foundation to JMM. Radioligand binding studies were generously performed by the NIMH Psychoactive Drug Screening Program, contract # HHSN-271-2008-00025-C. The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA.

Keywords

  • Alpha9alpha10
  • Analgesia
  • Nicotinic acetylcholine receptor
  • Pain

ASJC Scopus subject areas

  • Pharmacology

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