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

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 α4β2 nAChR (K i = 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 [ 3 H]dopamine release from rat striatal slices with an EC 50 of 10 ± 2 μM (250-fold less potent and 70% as efficacious as (−)-nicotine), an effect blocked by the nAChR antagonist dihydro-β-erythroidine. However, GTS-21 did not stimulate human α4β2 nor human ganglionic nAChRs significantly. In vivo, GTS-21 had no adverse effect 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 nmol/kg, i.m.).