TY  - JOUR
AU  - Obradović, Aleksandar
AU  - Joksimović, Srđan
AU  - Poe, Michael M.
AU  - Ramerstorfer, Joachim
AU  - Varagić, Zdravko
AU  - Namjoshi, Ojas A.
AU  - Batinić, Bojan
AU  - Radulović, Tamara
AU  - Marković, Bojan
AU  - Roth, Brian L.
AU  - Sieghart, Werner
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2200
AB  - Enormous progress in understanding the role of four populations of benzodiazepine-sensitive GABA(A) receptors was paralleled by the puzzling findings suggesting that substantial separation of behavioral effects may be accomplished by apparently nonselective modulators. We report on SH-I-048A, a newly synthesized chiral positive modulator of GABAA receptors characterized by exceptional subnanomolar affinity, high efficacy and non-selectivity. Its influence on behavior was assessed in Wistar rats and contrasted to that obtained with 2 mg/kg diazepam. SH-I-048A reached micromolar concentrations in brain tissue, while the unbound fraction in brain homogenate was around 1.5%. The approximated electrophysiological responses, which estimated free concentrations of SH-I-048A or diazepam are able to elicit, suggested a similarity between the 10 mg/kg dose of the novel ligand and 2 mg/kg diazepam; however, SH-I-048A was relatively more active at and as-containing GABAA receptors. Behaviorally, SH-I-048A induced sedative, muscle relaxant and ataxic effects, reversed mechanical hyperalgesia 24 h after injury, while it was devoid of clear anxiolytic actions and did not affect water-maze performance. While lack of clear anxiolytic actions may be connected with an enhanced potentiation at al-containing GABAA receptors, the observed behavior in the rotarod, water maze and peripheral nerve injury tests was possibly affected by its prominent action at receptors containing the as subunit. The current results encourage further innovative approaches aimed at linking in vitro an in vivo data in order to help define fine-tuning mechanisms at four sensitive receptor populations that underlie subtle differences in behavioral profiles of benzodiazepine site ligands.
PB  - Elsevier Science BV, Amsterdam
T2  - Brain Research
T1  - Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects
VL  - 1554
SP  - 36
EP  - 48
DO  - 10.1016/j.brainres.2014.01.036
ER  - 

@article{
author = "Obradović, Aleksandar and Joksimović, Srđan and Poe, Michael M. and Ramerstorfer, Joachim and Varagić, Zdravko and Namjoshi, Ojas A. and Batinić, Bojan and Radulović, Tamara and Marković, Bojan and Roth, Brian L. and Sieghart, Werner and Cook, James M. and Savić, Miroslav",
year = "2014",
abstract = "Enormous progress in understanding the role of four populations of benzodiazepine-sensitive GABA(A) receptors was paralleled by the puzzling findings suggesting that substantial separation of behavioral effects may be accomplished by apparently nonselective modulators. We report on SH-I-048A, a newly synthesized chiral positive modulator of GABAA receptors characterized by exceptional subnanomolar affinity, high efficacy and non-selectivity. Its influence on behavior was assessed in Wistar rats and contrasted to that obtained with 2 mg/kg diazepam. SH-I-048A reached micromolar concentrations in brain tissue, while the unbound fraction in brain homogenate was around 1.5%. The approximated electrophysiological responses, which estimated free concentrations of SH-I-048A or diazepam are able to elicit, suggested a similarity between the 10 mg/kg dose of the novel ligand and 2 mg/kg diazepam; however, SH-I-048A was relatively more active at and as-containing GABAA receptors. Behaviorally, SH-I-048A induced sedative, muscle relaxant and ataxic effects, reversed mechanical hyperalgesia 24 h after injury, while it was devoid of clear anxiolytic actions and did not affect water-maze performance. While lack of clear anxiolytic actions may be connected with an enhanced potentiation at al-containing GABAA receptors, the observed behavior in the rotarod, water maze and peripheral nerve injury tests was possibly affected by its prominent action at receptors containing the as subunit. The current results encourage further innovative approaches aimed at linking in vitro an in vivo data in order to help define fine-tuning mechanisms at four sensitive receptor populations that underlie subtle differences in behavioral profiles of benzodiazepine site ligands.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Brain Research",
title = "Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects",
volume = "1554",
pages = "36-48",
doi = "10.1016/j.brainres.2014.01.036"
}

Obradović, A., Joksimović, S., Poe, M. M., Ramerstorfer, J., Varagić, Z., Namjoshi, O. A., Batinić, B., Radulović, T., Marković, B., Roth, B. L., Sieghart, W., Cook, J. M.,& Savić, M.. (2014). Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects. in Brain Research
Elsevier Science BV, Amsterdam., 1554, 36-48.
https://doi.org/10.1016/j.brainres.2014.01.036

Obradović A, Joksimović S, Poe MM, Ramerstorfer J, Varagić Z, Namjoshi OA, Batinić B, Radulović T, Marković B, Roth BL, Sieghart W, Cook JM, Savić M. Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects. in Brain Research. 2014;1554:36-48.
doi:10.1016/j.brainres.2014.01.036 .

Obradović, Aleksandar, Joksimović, Srđan, Poe, Michael M., Ramerstorfer, Joachim, Varagić, Zdravko, Namjoshi, Ojas A., Batinić, Bojan, Radulović, Tamara, Marković, Bojan, Roth, Brian L., Sieghart, Werner, Cook, James M., Savić, Miroslav, "Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects" in Brain Research, 1554 (2014):36-48,
https://doi.org/10.1016/j.brainres.2014.01.036 . .

TY  - JOUR
AU  - Joksimović, Srđan
AU  - Divljaković, Jovana
AU  - van Linn, Michael
AU  - Varagić, Zdravko
AU  - Brajković, Gordana
AU  - Milinković, Marija M.
AU  - Yin, Wenyuan
AU  - Timić, Tamara
AU  - Sieghart, Werner
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2028
AB  - Despite significant advances in understanding the role of benzodiazepine (BZ)-sensitive populations of GABA A receptors, containing the α 1 , α 2 , α 3 or α 5 subunit, factual substrates of BZ-induced learning and memory deficits are not yet fully elucidated. It was shown that α 1 -subunit affinity-selective antagonist Β-CCt almost completely abolished spatial learning deficits induced by diazepam (DZP) in the Morris water maze. We examined a novel, highly (105 fold) α 1 -subunit selective ligand-WYS8 (0.2, 1 and 10mg/kg), on its own and in combination with the non-selective agonist DZP (2mg/kg) or Β-CCt (5mg/kg) in the water maze in rats. The in vitro efficacy study revealed that WYS8 acts as α 1 -subtype selective weak partial positive modulator (40% potentiation at 100nM). Measurement of concentrations of WYS8 and DZP in rat serum and brain tissues suggested that they did not substantially cross-influence the respective disposition. In the water maze, DZP impaired spatial learning (acquisition trials) and memory (probe trial). WYS8 caused no effect per se, did not affect the overall influence of DZP on the water-maze performance and was devoid of any activity in this task when combined with Β-CCt. Nonetheless, an additional analysis of the latency to reach the platform and the total distance swam suggested that WYS8 addition attenuated the run-down of the spatial impairment induced by DZP at the end of acquisition trials. These results demonstrate a clear difference in the influence of an α 1 subtype-selective antagonist and a partial agonist on the effects of DZP on the water-maze acquisition.
T2  - European Neuropsychopharmacology
T1  - Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α 1 GABA A receptors
VL  - 23
IS  - 5
SP  - 390
EP  - 399
DO  - 10.1016/j.euroneuro.2012.05.003
ER  - 

@article{
author = "Joksimović, Srđan and Divljaković, Jovana and van Linn, Michael and Varagić, Zdravko and Brajković, Gordana and Milinković, Marija M. and Yin, Wenyuan and Timić, Tamara and Sieghart, Werner and Cook, James M. and Savić, Miroslav",
year = "2013",
abstract = "Despite significant advances in understanding the role of benzodiazepine (BZ)-sensitive populations of GABA A receptors, containing the α 1 , α 2 , α 3 or α 5 subunit, factual substrates of BZ-induced learning and memory deficits are not yet fully elucidated. It was shown that α 1 -subunit affinity-selective antagonist Β-CCt almost completely abolished spatial learning deficits induced by diazepam (DZP) in the Morris water maze. We examined a novel, highly (105 fold) α 1 -subunit selective ligand-WYS8 (0.2, 1 and 10mg/kg), on its own and in combination with the non-selective agonist DZP (2mg/kg) or Β-CCt (5mg/kg) in the water maze in rats. The in vitro efficacy study revealed that WYS8 acts as α 1 -subtype selective weak partial positive modulator (40% potentiation at 100nM). Measurement of concentrations of WYS8 and DZP in rat serum and brain tissues suggested that they did not substantially cross-influence the respective disposition. In the water maze, DZP impaired spatial learning (acquisition trials) and memory (probe trial). WYS8 caused no effect per se, did not affect the overall influence of DZP on the water-maze performance and was devoid of any activity in this task when combined with Β-CCt. Nonetheless, an additional analysis of the latency to reach the platform and the total distance swam suggested that WYS8 addition attenuated the run-down of the spatial impairment induced by DZP at the end of acquisition trials. These results demonstrate a clear difference in the influence of an α 1 subtype-selective antagonist and a partial agonist on the effects of DZP on the water-maze acquisition.",
journal = "European Neuropsychopharmacology",
title = "Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α 1 GABA A receptors",
volume = "23",
number = "5",
pages = "390-399",
doi = "10.1016/j.euroneuro.2012.05.003"
}

Joksimović, S., Divljaković, J., van Linn, M., Varagić, Z., Brajković, G., Milinković, M. M., Yin, W., Timić, T., Sieghart, W., Cook, J. M.,& Savić, M.. (2013). Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α 1 GABA A receptors. in European Neuropsychopharmacology, 23(5), 390-399.
https://doi.org/10.1016/j.euroneuro.2012.05.003

Joksimović S, Divljaković J, van Linn M, Varagić Z, Brajković G, Milinković MM, Yin W, Timić T, Sieghart W, Cook JM, Savić M. Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α 1 GABA A receptors. in European Neuropsychopharmacology. 2013;23(5):390-399.
doi:10.1016/j.euroneuro.2012.05.003 .

Joksimović, Srđan, Divljaković, Jovana, van Linn, Michael, Varagić, Zdravko, Brajković, Gordana, Milinković, Marija M., Yin, Wenyuan, Timić, Tamara, Sieghart, Werner, Cook, James M., Savić, Miroslav, "Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α 1 GABA A receptors" in European Neuropsychopharmacology, 23, no. 5 (2013):390-399,
https://doi.org/10.1016/j.euroneuro.2012.05.003 . .

TY  - JOUR
AU  - Joksimović, Srđan
AU  - Varagić, Zdravko
AU  - Kovacević, Jovana
AU  - van Linn, Michael
AU  - Milić, Marija
AU  - Rallapalli, Sundari
AU  - Timić, Tamara
AU  - Sieghart, Werner
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1839
AB  - Synthesis of ligands inactive or with low activity at alpha(1) GABA(A) receptors has become the key concept for development of novel, more tolerable benzodiazepine (BZ)-like drugs. WYS8, a remarkably (105 times) alpha(1)-subtype selective partial positive modulator, may serve as a pharmacological tool for refining the role of alpha(1) GABA(A) receptors in mediation of BZs' effects. Here, the effects of WYS8 on GABA-induced currents and on diazepam-induced potentiation of recombinant BZ-sensitive GABA(A) receptors were studied in more detail. In addition, the behavioral profile of WYS8 (0.2, 1, and 10 mg/kg i.p.), on its own and in combination with diazepam, was tested in the spontaneous locomotor activity, elevated plus maze, grip strength, rotarod, and pentylenetetrazole tests. WYS8, applied at an in vivo attainable concentration of 100 nM, reduced the stimulation of GABA currents by 1 mu M diazepam by 57 % at alpha(1)beta(3)gamma(2), but not at alpha(2)beta(3)gamma(2), alpha(3)beta(3)gamma(2), or alpha(5)beta(3)gamma(2) GABA(A) receptors. The administration of WYS8 alone induced negligible behavioral consequences. When combined with diazepam, WYS8 caused a reduction in sedation, muscle relaxation, and anticonvulsant activity, as compared with this BZ alone, whereas ataxia was preserved, and the anxiolytic effect of 2 mg/kg diazepam was unmasked. Hence, a partial instead of full activation at alpha(1) GABA(A) receptors did not necessarily result in the attenuation of the effects assumed to be mediated by activation of these receptors, or in the full preservation of the effects mediated by activation of other GABA(A) receptors. Thus, the role of alpha(1) GABA(A) receptors appears more complex than that proposed by genetic studies.
PB  - Springer, New York
T2  - QSAR & Combinatorial Science
T1  - Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?
VL  - 230
IS  - 1
SP  - 113
EP  - 123
DO  - 10.1007/s00213-013-3143-4
ER  - 

@article{
author = "Joksimović, Srđan and Varagić, Zdravko and Kovacević, Jovana and van Linn, Michael and Milić, Marija and Rallapalli, Sundari and Timić, Tamara and Sieghart, Werner and Cook, James M. and Savić, Miroslav",
year = "2013",
abstract = "Synthesis of ligands inactive or with low activity at alpha(1) GABA(A) receptors has become the key concept for development of novel, more tolerable benzodiazepine (BZ)-like drugs. WYS8, a remarkably (105 times) alpha(1)-subtype selective partial positive modulator, may serve as a pharmacological tool for refining the role of alpha(1) GABA(A) receptors in mediation of BZs' effects. Here, the effects of WYS8 on GABA-induced currents and on diazepam-induced potentiation of recombinant BZ-sensitive GABA(A) receptors were studied in more detail. In addition, the behavioral profile of WYS8 (0.2, 1, and 10 mg/kg i.p.), on its own and in combination with diazepam, was tested in the spontaneous locomotor activity, elevated plus maze, grip strength, rotarod, and pentylenetetrazole tests. WYS8, applied at an in vivo attainable concentration of 100 nM, reduced the stimulation of GABA currents by 1 mu M diazepam by 57 % at alpha(1)beta(3)gamma(2), but not at alpha(2)beta(3)gamma(2), alpha(3)beta(3)gamma(2), or alpha(5)beta(3)gamma(2) GABA(A) receptors. The administration of WYS8 alone induced negligible behavioral consequences. When combined with diazepam, WYS8 caused a reduction in sedation, muscle relaxation, and anticonvulsant activity, as compared with this BZ alone, whereas ataxia was preserved, and the anxiolytic effect of 2 mg/kg diazepam was unmasked. Hence, a partial instead of full activation at alpha(1) GABA(A) receptors did not necessarily result in the attenuation of the effects assumed to be mediated by activation of these receptors, or in the full preservation of the effects mediated by activation of other GABA(A) receptors. Thus, the role of alpha(1) GABA(A) receptors appears more complex than that proposed by genetic studies.",
publisher = "Springer, New York",
journal = "QSAR & Combinatorial Science",
title = "Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?",
volume = "230",
number = "1",
pages = "113-123",
doi = "10.1007/s00213-013-3143-4"
}

Joksimović, S., Varagić, Z., Kovacević, J., van Linn, M., Milić, M., Rallapalli, S., Timić, T., Sieghart, W., Cook, J. M.,& Savić, M.. (2013). Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?. in QSAR & Combinatorial Science
Springer, New York., 230(1), 113-123.
https://doi.org/10.1007/s00213-013-3143-4

Joksimović S, Varagić Z, Kovacević J, van Linn M, Milić M, Rallapalli S, Timić T, Sieghart W, Cook JM, Savić M. Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?. in QSAR & Combinatorial Science. 2013;230(1):113-123.
doi:10.1007/s00213-013-3143-4 .

Joksimović, Srđan, Varagić, Zdravko, Kovacević, Jovana, van Linn, Michael, Milić, Marija, Rallapalli, Sundari, Timić, Tamara, Sieghart, Werner, Cook, James M., Savić, Miroslav, "Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?" in QSAR & Combinatorial Science, 230, no. 1 (2013):113-123,
https://doi.org/10.1007/s00213-013-3143-4 . .