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 comp ound that interacts with rat neuronal nicotinic acetylcholine receptor s (nAChRs), was evaluated using human recombinant nAChRs in vitro and various pharmacokinetic and behavioral models in rodents, dogs and mon keys. GTS-21 bound to human alpha 4 beta 2 nAChR (K-i = 20 nM) 100-fol d more potently than to human alpha 7 nAChR, and was 18- and 2-fold le ss potent than (-)-nicotine at human alpha 4 beta 2 and alpha 7 nAChR, respectively. Functionally, GTS-21 stimulated [H-3]dopamine release f rom rat striatal slices with an EC50 of 10 +/- 2 mu M (250-fold less p otent and 70% as efficacious as (-)-nicotine), an effect blocked by th e nAChR antagonist dihydro-beta-erythroidine. However, GTS-21 did not stimulate human alpha 4 beta 2 nor human ganglionic nAChRs significant ly. In vivo, GTS-21 had no adverse effect on dog blood pressure (less than or equal to 2.5 mu mol/kg i.v. bolus infusion), in marked contras t with (-)-nicotine. GTS-21 (less than or equal to 62 mu mol/kg, s.c.) also did not cross-discriminate significantly with (-)-nicotine in ra ts and did not reduce temperature or locomotion in mice. Neither was i t active in the elevated plus maze anxiety model (0.19-6.2 mu mol/kg, IP) in normal mice. However, GTS-21 did improve learning performance o f monkeys in the delayed matching-to-sample task (32-130 mnol/kg, i.m. ). (C) 1997 Elsevier Science Inc.