Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo

Clark A. Briggs, David J. Anderson, Jorge D. Brioni, Jerry J. Buccafusco, Michael J. Buckley, Jeffrey E. Campbell, Michael W. Decker, Diana Donnelly-Roberts, Richard L. Elliott, Murali Gopalakrishnan, Mark W. Holladay, Yu Hua Hui, William J. Jackson, David J.B. Kim, Kennan C. Marsh, Alyssa O'Neill, Mark A. Prendergast, Keith B. Ryther, James P. Sullivan, Stephen P. Arneric

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198 Scopus citations


(2,4)-Dimethoxybenzylidene anabaseine dihydrochloride (GTS-21), a compound that interacts with rat neuronal nicotinic acetylcholine receptors (nAChRs), was evaluated using human recombinant nAChRs in vitro and various pharmacokinetic and behavioral models in rodents, dogs and monkeys. GTS-21 bound to human α4β2 nAChR (K1 = 20 nM) 100-fold more potently than to human α7 nAChR, and was 18- and 2-fold less potent than (-)-nicotine at human α4β2 and α7 nAChR, respectively. Functionally, GTS-21 stimulated [3H]dopamine release from rat striatal slices with an EC50 of 10 μM (250-fold less potent and 70% as efficacious as (-)-nicotine)., an effect blocked by the nAChR antagonist dihydro-β-crythroidine. However, on dog blood pressure (≤2.5 μmol/kg i.v. bolus infusion), in marked contrast with (-)-nicotine. GTS-21 (≤62 μmol/kg. s.c.)also did not cross-discriminate significantly with (-)-nicotine in rats and did not reduce temperature or locomotion in mice. Neither was it active in the elevated plus maze anxiety model (0.19-6.2 μmol/kg, IP) in normal mice. However, GTS-21 did improve learning performance of monkeys in the delayed matching-to-sample task (32- 130 μmol/kg. i.m.).

Original languageEnglish
Pages (from-to)231-241
Number of pages11
JournalPharmacology Biochemistry and Behavior
Issue number1-2
StatePublished - May 1997


  • Anabaseine
  • Anxiety
  • GTS-21
  • Human
  • Learning
  • Monkey
  • Mouse
  • Nicotine
  • Nicotinic receptors
  • Pharmacokinetics
  • Rat
  • Toxicity

ASJC Scopus subject areas

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Clinical Biochemistry
  • Biological Psychiatry
  • Behavioral Neuroscience


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