TY - JOUR
T1 - Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo
AU - Briggs, Clark A.
AU - Anderson, David J.
AU - Brioni, Jorge D.
AU - Buccafusco, Jerry J.
AU - Buckley, Michael J.
AU - Campbell, Jeffrey E.
AU - Decker, Michael W.
AU - Donnelly-Roberts, Diana
AU - Elliott, Richard L.
AU - Gopalakrishnan, Murali
AU - Holladay, Mark W.
AU - Hui, Yu Hua
AU - Jackson, William J.
AU - Kim, David J.B.
AU - Marsh, Kennan C.
AU - O'Neill, Alyssa
AU - Prendergast, Mark A.
AU - Ryther, Keith B.
AU - Sullivan, James P.
AU - Arneric, Stephen P.
PY - 1997/5
Y1 - 1997/5
N2 - (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.).
AB - (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.).
KW - Anabaseine
KW - Anxiety
KW - GTS-21
KW - Human
KW - Learning
KW - Monkey
KW - Mouse
KW - Nicotine
KW - Nicotinic receptors
KW - Pharmacokinetics
KW - Rat
KW - Toxicity
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U2 - 10.1016/S0091-3057(96)00354-1
DO - 10.1016/S0091-3057(96)00354-1
M3 - Article
C2 - 9164577
AN - SCOPUS:0031003185
SN - 0091-3057
VL - 57
SP - 231
EP - 241
JO - Pharmacology Biochemistry and Behavior
JF - Pharmacology Biochemistry and Behavior
IS - 1-2
ER -