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

Pharmacol Biochem Behav. May-Jun 1997;57(1-2):231-41. doi: 10.1016/s0091-3057(96)00354-1.

Abstract

(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 alpha 4 beta 2 nAChR (K1-20 nM) 100-fold more potently than to human alpha 7 nAChR, and was 18- and 2-fold less potent than (-)-nicotine at human alpha 4 beta 2 and alpha 7 nAChR, respectively. Functionally. GTS-21 stimulated [5H]dopamine release from rat striatal slices with an EC50 of 10 +/- 2 microM (250-fold less potent and 70% as efficacious as (-)-nicotine), an effect blocked by the nAChR antagonist dihydro-beta-erythroidine. However, GTS-21 did not stimulate human alpha 4 beta 2 nor human ganglionic nAChRs significantly. In vivo, GTS-21 had no adverse effect on dog blood pressure (< or = 2.5 micromol/kg i.v. bolus infusion), in marked contrast with (-)-nicotine, GTS-21 (-62 micromol/kg.s.e.) 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 micromol/kg.IP) in normal mice. However, GTS-21 did improve learning performance of monkeys in the delayed matching-to-sample task (32-130 nmol/kg.i.m.).

MeSH terms

  • Animals
  • Anti-Anxiety Agents / metabolism*
  • Anti-Anxiety Agents / pharmacokinetics
  • Anti-Anxiety Agents / toxicity
  • Behavior, Animal / drug effects
  • Benzylidene Compounds / metabolism*
  • Benzylidene Compounds / pharmacokinetics
  • Benzylidene Compounds / toxicity
  • Cloning, Molecular
  • Dogs
  • Ganglia / metabolism*
  • Humans
  • In Vitro Techniques
  • Macaca fascicularis
  • Macaca nemestrina
  • Male
  • Mice
  • Mice, Inbred Strains
  • Neurons / metabolism*
  • Nicotinic Agonists / metabolism*
  • Nicotinic Agonists / pharmacokinetics
  • Nicotinic Agonists / toxicity
  • Pyridines / metabolism*
  • Pyridines / pharmacokinetics
  • Pyridines / toxicity
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, Nicotinic / metabolism*

Substances

  • Anti-Anxiety Agents
  • Benzylidene Compounds
  • Nicotinic Agonists
  • Pyridines
  • Receptors, Nicotinic
  • 3-(2,4-dimethoxybenzylidene)anabaseine