TY  - JOUR
AU  - Savić, Miroslav
AU  - Majumder, Samarpan
AU  - Huang, Shengming
AU  - Edwankar, Rahul V.
AU  - Furtmueller, Roman
AU  - Joksimović, Srđan
AU  - Clayton, Terry
AU  - Ramerstorfer, Joachim
AU  - Milinković, Marija M.
AU  - Roth, Bryan L.
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2010
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1380
AB  - Over the last years, genetic studies have greatly improved Our knowledge on the receptor subtypes mediating various pharmacological effects of positive allosteric modulators at GABA(A) receptors. This stimulated the development of new benzodiazepine (BZ)-like ligands, especially those inactive/low-active at GABA(A) receptors containing the alpha(1) subunit, with the aim of generating more selective drugs. Hereby, the affinity and efficacy of four recently synthesized BZ site ligands: SH-053-2'N, SH-053-S-CH3-2'F, SH-053-R-CH3-2'F and JY-XHe-053 were assessed. They were also studied in behavioral tests of spontaneous locomotor activity, elevated plus maze, and water maze in rats, which are considered predictive of. respectively, the sedative, anxiolytic, and amnesic influence of BZs. The novel ligands had moderately low to low affinity and mild to partial agonistic efficacy at GABA(A) receptors containing the a, subunit, with variable, but more pronounced efficacy at other BZ-sensitive binding sites. While presumably alpha(1) receptor-mediated sedative effects of GABA(A) modulation were not fully eliminated with any of the ligands tested, only SH-053-2'N and SH-053-S-CH3-2'F, both dosed at 30 mg/kg, exerted anxiolytic effects. The lack of clear anxiolytic-like activity of JY-XHe-053, despite its efficacy at alpha(2)- and alpha(3)-GABA(A) receptors, may have been partly connected with its preferential affinity at alpha(5)-GABA(A) receptors coupled with weak agonist activity at alpha(1)-containing subtypes. The memory impairment in water-maze experiments, generally reported with BZ site agonists, was completely circumvented with all four ligands. The results suggest that a substantial amount of activity at a I GABA(A) receptors is needed for affecting spatial learning and memory impairments, while much weaker activity at alpha(1) and alpha(5)-GABA(A) receptors is sufficient for eliciting sedation.
PB  - Pergamon-Elsevier Science Ltd, Oxford
T2  - Progress in Nutrition
T1  - Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at alpha 1 plus alpha 5 versus alpha 2 plus alpha 3 subunits account for dissimilarities in behavioral effects in rats?
VL  - 34
IS  - 2
SP  - 376
EP  - 386
DO  - 10.1016/j.pnpbp.2010.01.004
ER  - 

@article{
author = "Savić, Miroslav and Majumder, Samarpan and Huang, Shengming and Edwankar, Rahul V. and Furtmueller, Roman and Joksimović, Srđan and Clayton, Terry and Ramerstorfer, Joachim and Milinković, Marija M. and Roth, Bryan L. and Sieghart, Werner and Cook, James M.",
year = "2010",
abstract = "Over the last years, genetic studies have greatly improved Our knowledge on the receptor subtypes mediating various pharmacological effects of positive allosteric modulators at GABA(A) receptors. This stimulated the development of new benzodiazepine (BZ)-like ligands, especially those inactive/low-active at GABA(A) receptors containing the alpha(1) subunit, with the aim of generating more selective drugs. Hereby, the affinity and efficacy of four recently synthesized BZ site ligands: SH-053-2'N, SH-053-S-CH3-2'F, SH-053-R-CH3-2'F and JY-XHe-053 were assessed. They were also studied in behavioral tests of spontaneous locomotor activity, elevated plus maze, and water maze in rats, which are considered predictive of. respectively, the sedative, anxiolytic, and amnesic influence of BZs. The novel ligands had moderately low to low affinity and mild to partial agonistic efficacy at GABA(A) receptors containing the a, subunit, with variable, but more pronounced efficacy at other BZ-sensitive binding sites. While presumably alpha(1) receptor-mediated sedative effects of GABA(A) modulation were not fully eliminated with any of the ligands tested, only SH-053-2'N and SH-053-S-CH3-2'F, both dosed at 30 mg/kg, exerted anxiolytic effects. The lack of clear anxiolytic-like activity of JY-XHe-053, despite its efficacy at alpha(2)- and alpha(3)-GABA(A) receptors, may have been partly connected with its preferential affinity at alpha(5)-GABA(A) receptors coupled with weak agonist activity at alpha(1)-containing subtypes. The memory impairment in water-maze experiments, generally reported with BZ site agonists, was completely circumvented with all four ligands. The results suggest that a substantial amount of activity at a I GABA(A) receptors is needed for affecting spatial learning and memory impairments, while much weaker activity at alpha(1) and alpha(5)-GABA(A) receptors is sufficient for eliciting sedation.",
publisher = "Pergamon-Elsevier Science Ltd, Oxford",
journal = "Progress in Nutrition",
title = "Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at alpha 1 plus alpha 5 versus alpha 2 plus alpha 3 subunits account for dissimilarities in behavioral effects in rats?",
volume = "34",
number = "2",
pages = "376-386",
doi = "10.1016/j.pnpbp.2010.01.004"
}

Savić, M., Majumder, S., Huang, S., Edwankar, R. V., Furtmueller, R., Joksimović, S., Clayton, T., Ramerstorfer, J., Milinković, M. M., Roth, B. L., Sieghart, W.,& Cook, J. M.. (2010). Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at alpha 1 plus alpha 5 versus alpha 2 plus alpha 3 subunits account for dissimilarities in behavioral effects in rats?. in Progress in Nutrition
Pergamon-Elsevier Science Ltd, Oxford., 34(2), 376-386.
https://doi.org/10.1016/j.pnpbp.2010.01.004

Savić M, Majumder S, Huang S, Edwankar RV, Furtmueller R, Joksimović S, Clayton T, Ramerstorfer J, Milinković MM, Roth BL, Sieghart W, Cook JM. Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at alpha 1 plus alpha 5 versus alpha 2 plus alpha 3 subunits account for dissimilarities in behavioral effects in rats?. in Progress in Nutrition. 2010;34(2):376-386.
doi:10.1016/j.pnpbp.2010.01.004 .

Savić, Miroslav, Majumder, Samarpan, Huang, Shengming, Edwankar, Rahul V., Furtmueller, Roman, Joksimović, Srđan, Clayton, Terry, Ramerstorfer, Joachim, Milinković, Marija M., Roth, Bryan L., Sieghart, Werner, Cook, James M., "Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at alpha 1 plus alpha 5 versus alpha 2 plus alpha 3 subunits account for dissimilarities in behavioral effects in rats?" in Progress in Nutrition, 34, no. 2 (2010):376-386,
https://doi.org/10.1016/j.pnpbp.2010.01.004 . .