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

(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.).