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

Clark A. Briggs; David J. Anderson; Jorge D. Brioni; Jerry J. Buccafusco; Michael J. Buckley; Jeffrey E. Campbell; Michael W. Decker; Diana Donnelly-Roberts; Richard L. Elliott; Murali Gopalakrishnan; Mark W. Holladay; Yu Hua Hui; William J. Jackson; David J.B. Kim; Kennan C. Marsh; Alyssa O'Neill; Mark A. Prendergast; Keith B. Ryther; James P. Sullivan; Stephen P. Arneric

doi:10.1016/S0091-3057(96)00354-1

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

Clark A. Briggs, David J. Anderson, Jorge D. Brioni, Jerry J. Buccafusco, Michael J. Buckley, Jeffrey E. Campbell, Michael W. Decker, Diana Donnelly-Roberts, Richard L. Elliott, Murali Gopalakrishnan, Mark W. Holladay, Yu Hua Hui, William J. Jackson, David J.B. Kim, Kennan C. Marsh, Alyssa O'Neill, Mark A. Prendergast, Keith B. Ryther, James P. Sullivan, Stephen P. Arneric

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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 (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.).

Original language	English
Pages (from-to)	231-241
Number of pages	11
Journal	Pharmacology Biochemistry and Behavior
Volume	57
Issue number	1-2
DOIs	https://doi.org/10.1016/S0091-3057(96)00354-1
State	Published - May 1997

Keywords

Anabaseine
Anxiety
GTS-21
Human
Learning
Monkey
Mouse
Nicotine
Nicotinic receptors
Pharmacokinetics
Rat
Toxicity

ASJC Scopus subject areas

Biochemistry
Toxicology
Pharmacology
Clinical Biochemistry
Biological Psychiatry
Behavioral Neuroscience

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10.1016/S0091-3057(96)00354-1

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Briggs, C. A., Anderson, D. J., Brioni, J. D., Buccafusco, J. J., Buckley, M. J., Campbell, J. E., Decker, M. W., Donnelly-Roberts, D., Elliott, R. L., Gopalakrishnan, M., Holladay, M. W., Hui, Y. H., Jackson, W. J., Kim, D. J. B., Marsh, K. C., O'Neill, A., Prendergast, M. A., Ryther, K. B., Sullivan, J. P., & Arneric, S. P. (1997). Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo. Pharmacology Biochemistry and Behavior, 57(1-2), 231-241. https://doi.org/10.1016/S0091-3057(96)00354-1

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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 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.).",

keywords = "Anabaseine, Anxiety, GTS-21, Human, Learning, Monkey, Mouse, Nicotine, Nicotinic receptors, Pharmacokinetics, Rat, Toxicity",

author = "Briggs, {Clark A.} and Anderson, {David J.} and Brioni, {Jorge D.} and Buccafusco, {Jerry J.} and Buckley, {Michael J.} and Campbell, {Jeffrey E.} and Decker, {Michael W.} and Diana Donnelly-Roberts and Elliott, {Richard L.} and Murali Gopalakrishnan and Holladay, {Mark W.} and Hui, {Yu Hua} and Jackson, {William J.} and Kim, {David J.B.} and Marsh, {Kennan C.} and Alyssa O'Neill and Prendergast, {Mark A.} and Ryther, {Keith B.} and Sullivan, {James P.} and Arneric, {Stephen P.}",

year = "1997",

month = may,

doi = "10.1016/S0091-3057(96)00354-1",

language = "English",

volume = "57",

pages = "231--241",

number = "1-2",

}

Briggs, CA, Anderson, DJ, Brioni, JD, Buccafusco, JJ, Buckley, MJ, Campbell, JE, Decker, MW, Donnelly-Roberts, D, Elliott, RL, Gopalakrishnan, M, Holladay, MW, Hui, YH, Jackson, WJ, Kim, DJB, Marsh, KC, O'Neill, A, Prendergast, MA, Ryther, KB, Sullivan, JP & Arneric, SP 1997, 'Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo', Pharmacology Biochemistry and Behavior, vol. 57, no. 1-2, pp. 231-241. https://doi.org/10.1016/S0091-3057(96)00354-1

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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UR - http://www.scopus.com/inward/citedby.url?scp=0031003185&partnerID=8YFLogxK

U2 - 10.1016/S0091-3057(96)00354-1

DO - 10.1016/S0091-3057(96)00354-1

M3 - Article

C2 - 9164577

AN - SCOPUS:0031003185

VL - 57

SP - 231

EP - 241

IS - 1-2

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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