title: 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 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.).
authors.affiliation: Abbott Laboratories, Abbott Park, Illinois 60064, USA. clark.briggs@abbott.com
authors.forename: C A
authors.initials: CA
authors.lastname: Briggs
authors.forename: D J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: J D
authors.initials: JD
authors.lastname: Brioni
authors.forename: J J
authors.initials: JJ
authors.lastname: Buccafusco
authors.forename: M J
authors.initials: MJ
authors.lastname: Buckley
authors.forename: J E
authors.initials: JE
authors.lastname: Campbell
authors.forename: M W
authors.initials: MW
authors.lastname: Decker
authors.forename: D
authors.initials: D
authors.lastname: Donnelly-Roberts
authors.forename: R L
authors.initials: RL
authors.lastname: Elliott
authors.forename: M
authors.initials: M
authors.lastname: Gopalakrishnan
authors.forename: M W
authors.initials: MW
authors.lastname: Holladay
authors.forename: Y H
authors.initials: YH
authors.lastname: Hui
authors.forename: W J
authors.initials: WJ
authors.lastname: Jackson
authors.forename: D J
authors.initials: DJ
authors.lastname: Kim
authors.forename: K C
authors.initials: KC
authors.lastname: Marsh
authors.forename: A
authors.initials: A
authors.lastname: O'Neill
authors.forename: M A
authors.initials: MA
authors.lastname: Prendergast
authors.forename: K B
authors.initials: KB
authors.lastname: Ryther
authors.forename: J P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: S P
authors.initials: SP
authors.lastname: Arneric
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects; D001597:Benzylidene Compounds / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D003001:Cloning, Molecular; D004285:Dogs; D005724:Ganglia / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008254:Macaca nemestrina; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D011725:Pyridines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D014151:Anti-Anxiety Agents; D001597:Benzylidene Compounds; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C088936:3-(2,4-dimethoxybenzylidene)anabaseine