TY  - JOUR
AU  - Savić, Miroslav
AU  - Clayton, Terry
AU  - Furtmueller, Roman
AU  - Gaurilović, Ivana
AU  - Samardžić, Janko
AU  - Savić, Snežana
AU  - Huck, Sigismund
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2008
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1081
AB  - Benzodiazepine (BZ) site ligands affect vigilance, anxiety, memory processes, muscle tone and epileptogenic propensity through modulation of neurotransmission at GABA(A) receptors containing alpha 1, alpha 2, alpha 3 or alpha 5 subunits, and may have numerous experimental and clinical applications. The ability of non-selective BZ site inverse agonists to enhance cognition, documented in animal models and human studies, is clinically not feasible due to potentially unacceptable psychomotor effects. Most investigations to date have proposed the alpha 1 and/or alpha 5 subunit-containing GABA(A) receptors as comprising the memory-modulating population of these receptors. The novel ligand PWZ-029, which we synthesized and characterized electrophysiologically, possesses in vitro binding selectivity and moderate inverse agonist functional selectivity at alpha 5-containing GABA(A) receptors. This ligand has also been examined in rats in the passive and active avoidance, spontaneous locomotor activity, elevated plus maze and grip strength tests, primarily predictive of the effects on the memory acquisition, basal locomotor activity, anxiety level and muscle tone, respectively. The improvement of task learning was detected at the dose of 5 mg/kg in the passive, but not active avoidance test. The inverse agonist PWZ-029 had no effect on anxiety or muscle tone, whereas at higher doses (10 and 20 mg/kg) it decreased locomotor activity. This effect was antagonized by flumazenil. and also by the lower (but not the higher) dose of an agonist (SH-053-R-CH3-2'F) selective for GABA(A) receptors containing the alpha 5 subunit. The hypolocomotor effect of PWZ-029 was not antagonized by the antagonist beta-CCt exhibiting a preferential affinity for alpha 1-subunit-containing receptors. These data suggest that moderate negative modulation at GABA(A) receptors containing the alpha 5 subunit is a sufficient condition for eliciting enhanced encoding/consolidation of declarative memory, while the influence of higher doses of modulators at these receptors on motor activity shows an intricate pattern whose relevance and mechanism await to be defined.
PB  - Elsevier Science BV, Amsterdam
T2  - Brain Research
T1  - PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha 5 subunits, improves passive, but not active, avoidance learning in rats
VL  - 1208
SP  - 150
EP  - 159
DO  - 10.1016/j.brainres.2008.02.020
ER  - 

@article{
author = "Savić, Miroslav and Clayton, Terry and Furtmueller, Roman and Gaurilović, Ivana and Samardžić, Janko and Savić, Snežana and Huck, Sigismund and Sieghart, Werner and Cook, James M.",
year = "2008",
abstract = "Benzodiazepine (BZ) site ligands affect vigilance, anxiety, memory processes, muscle tone and epileptogenic propensity through modulation of neurotransmission at GABA(A) receptors containing alpha 1, alpha 2, alpha 3 or alpha 5 subunits, and may have numerous experimental and clinical applications. The ability of non-selective BZ site inverse agonists to enhance cognition, documented in animal models and human studies, is clinically not feasible due to potentially unacceptable psychomotor effects. Most investigations to date have proposed the alpha 1 and/or alpha 5 subunit-containing GABA(A) receptors as comprising the memory-modulating population of these receptors. The novel ligand PWZ-029, which we synthesized and characterized electrophysiologically, possesses in vitro binding selectivity and moderate inverse agonist functional selectivity at alpha 5-containing GABA(A) receptors. This ligand has also been examined in rats in the passive and active avoidance, spontaneous locomotor activity, elevated plus maze and grip strength tests, primarily predictive of the effects on the memory acquisition, basal locomotor activity, anxiety level and muscle tone, respectively. The improvement of task learning was detected at the dose of 5 mg/kg in the passive, but not active avoidance test. The inverse agonist PWZ-029 had no effect on anxiety or muscle tone, whereas at higher doses (10 and 20 mg/kg) it decreased locomotor activity. This effect was antagonized by flumazenil. and also by the lower (but not the higher) dose of an agonist (SH-053-R-CH3-2'F) selective for GABA(A) receptors containing the alpha 5 subunit. The hypolocomotor effect of PWZ-029 was not antagonized by the antagonist beta-CCt exhibiting a preferential affinity for alpha 1-subunit-containing receptors. These data suggest that moderate negative modulation at GABA(A) receptors containing the alpha 5 subunit is a sufficient condition for eliciting enhanced encoding/consolidation of declarative memory, while the influence of higher doses of modulators at these receptors on motor activity shows an intricate pattern whose relevance and mechanism await to be defined.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Brain Research",
title = "PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha 5 subunits, improves passive, but not active, avoidance learning in rats",
volume = "1208",
pages = "150-159",
doi = "10.1016/j.brainres.2008.02.020"
}

Savić, M., Clayton, T., Furtmueller, R., Gaurilović, I., Samardžić, J., Savić, S., Huck, S., Sieghart, W.,& Cook, J. M.. (2008). PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha 5 subunits, improves passive, but not active, avoidance learning in rats. in Brain Research
Elsevier Science BV, Amsterdam., 1208, 150-159.
https://doi.org/10.1016/j.brainres.2008.02.020

Savić M, Clayton T, Furtmueller R, Gaurilović I, Samardžić J, Savić S, Huck S, Sieghart W, Cook JM. PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha 5 subunits, improves passive, but not active, avoidance learning in rats. in Brain Research. 2008;1208:150-159.
doi:10.1016/j.brainres.2008.02.020 .

Savić, Miroslav, Clayton, Terry, Furtmueller, Roman, Gaurilović, Ivana, Samardžić, Janko, Savić, Snežana, Huck, Sigismund, Sieghart, Werner, Cook, James M., "PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha 5 subunits, improves passive, but not active, avoidance learning in rats" in Brain Research, 1208 (2008):150-159,
https://doi.org/10.1016/j.brainres.2008.02.020 . .

TY  - JOUR
AU  - Savić, Miroslav
AU  - Huang, Shengming
AU  - Furtmueller, Roman
AU  - Clayton, Terry
AU  - Huck, Sigismund
AU  - Obradović, Dragan I.
AU  - Ugrešić, Nenad
AU  - Sieghart, Werner
AU  - Bokonjić, Dubravko
AU  - Cook, James M.
PY  - 2008
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1048
AB  - Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA(A) receptors containing alpha(1), alpha(2), alpha(3) or alpha(5) subunits. Genetic studies suggest that modulation at the alpha(1) subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABAA receptors containing the alpha(1) subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABAA receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for alpha(2)-, alpha(3)-, and alpha(5)-containing subtypes of GABA(A) receptors (SH-053-S-CH3 and SH-053-S-CH3-2'F) or essentially selective for alpha(5) subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of alpha(1) subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2'F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by alpha(5)-containing GABAA receptors. Hence, it could be of importance to avoid substantial agonist activity at alpha(5) receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.
PB  - Nature Publishing Group, London
T2  - Neuropsychopharmacology
T1  - Are GABA(A) receptors containing alpha 5 Subunits contributing to the sedative properties of benzodiazepine site agonists?
VL  - 33
IS  - 2
SP  - 332
EP  - 339
DO  - 10.1038/sj.npp.1301403
ER  - 

@article{
author = "Savić, Miroslav and Huang, Shengming and Furtmueller, Roman and Clayton, Terry and Huck, Sigismund and Obradović, Dragan I. and Ugrešić, Nenad and Sieghart, Werner and Bokonjić, Dubravko and Cook, James M.",
year = "2008",
abstract = "Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA(A) receptors containing alpha(1), alpha(2), alpha(3) or alpha(5) subunits. Genetic studies suggest that modulation at the alpha(1) subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABAA receptors containing the alpha(1) subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABAA receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for alpha(2)-, alpha(3)-, and alpha(5)-containing subtypes of GABA(A) receptors (SH-053-S-CH3 and SH-053-S-CH3-2'F) or essentially selective for alpha(5) subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of alpha(1) subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2'F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by alpha(5)-containing GABAA receptors. Hence, it could be of importance to avoid substantial agonist activity at alpha(5) receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.",
publisher = "Nature Publishing Group, London",
journal = "Neuropsychopharmacology",
title = "Are GABA(A) receptors containing alpha 5 Subunits contributing to the sedative properties of benzodiazepine site agonists?",
volume = "33",
number = "2",
pages = "332-339",
doi = "10.1038/sj.npp.1301403"
}

Savić, M., Huang, S., Furtmueller, R., Clayton, T., Huck, S., Obradović, D. I., Ugrešić, N., Sieghart, W., Bokonjić, D.,& Cook, J. M.. (2008). Are GABA(A) receptors containing alpha 5 Subunits contributing to the sedative properties of benzodiazepine site agonists?. in Neuropsychopharmacology
Nature Publishing Group, London., 33(2), 332-339.
https://doi.org/10.1038/sj.npp.1301403

Savić M, Huang S, Furtmueller R, Clayton T, Huck S, Obradović DI, Ugrešić N, Sieghart W, Bokonjić D, Cook JM. Are GABA(A) receptors containing alpha 5 Subunits contributing to the sedative properties of benzodiazepine site agonists?. in Neuropsychopharmacology. 2008;33(2):332-339.
doi:10.1038/sj.npp.1301403 .

Savić, Miroslav, Huang, Shengming, Furtmueller, Roman, Clayton, Terry, Huck, Sigismund, Obradović, Dragan I., Ugrešić, Nenad, Sieghart, Werner, Bokonjić, Dubravko, Cook, James M., "Are GABA(A) receptors containing alpha 5 Subunits contributing to the sedative properties of benzodiazepine site agonists?" in Neuropsychopharmacology, 33, no. 2 (2008):332-339,
https://doi.org/10.1038/sj.npp.1301403 . .