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 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.).
Briggs
C A
CA
Abbott Laboratories, Abbott Park, Illinois 60064, USA. clark.briggs@abbott.com
Anderson
D J
DJ
Brioni
J D
JD
Buccafusco
J J
JJ
Buckley
M J
MJ
Campbell
J E
JE
Decker
M W
MW
Donnelly-Roberts
D
D
Elliott
R L
RL
Gopalakrishnan
M
M
Holladay
M W
MW
Hui
Y H
YH
Jackson
W J
WJ
Kim
D J
DJ
Marsh
K C
KC
O'Neill
A
A
Prendergast
M A
MA
Ryther
K B
KB
Sullivan
J P
JP
Arneric
S P
SP
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*
D014151:Anti-Anxiety Agents; D001597:Benzylidene Compounds; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C088936:3-(2,4-dimethoxybenzylidene)anabaseine