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  - Đorđević, Sanela
AU  - Radulović, Tamara
AU  - Cekić, Nebojša
AU  - Ranđelović, Danijela
AU  - Savić, Miroslav
AU  - Krajišnik, Danina
AU  - Milić, Jela
AU  - Savić, Snežana
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1873
AB  - With the aid of experimental design, we developed and characterized nanoemulsions for parenteral drug delivery. Formulations containing a mixture of medium-chain triglycerides and soybean oil as oil phase, lecithin (soybean/egg) and polysorbate 80 as emulsifiers, and 0.1M phosphate buffer solution (pH 8) as aqueous phase were prepared by cold high-pressure homogenization. To study the effects of the oil content, lecithin type, and the presence of diazepam as a model drug and their interactions on physicochemical characteristics of nanoemulsions, a three factor two-level full factorial design was applied. The nanoemulsions were evaluated concerning droplet size and size distribution, surface charge, viscosity, morphology, drug-excipient interactions, and physical stability. The characterization revealed the small spherical droplets in the range 195-220nm with polydispersity index below 0.15 and zeta potential between -30 and -60mV. Interactions among the investigated factors, rather than factors alone, were shown to more profoundly affect nanoemulsion characteristics. In vivo pharmacokinetic study of selected diazepam nanoemulsions with different oil content (20%, 30%, and 40%, w/w) demonstrated fast and intense initial distribution into rat brain of diazepam from nanoemulsions with 20% and 30% (w/w) oil content, suggesting their applicability in urgent situations.
PB  - Wiley-Blackwell, Hoboken
T2  - Journal of Pharmaceutical Sciences
T1  - Experimental Design in Formulation of Diazepam Nanoemulsions: Physicochemical and Pharmacokinetic Performances
VL  - 102
IS  - 11
SP  - 4159
EP  - 4172
DO  - 10.1002/jps.23734
ER  - 

@article{
author = "Đorđević, Sanela and Radulović, Tamara and Cekić, Nebojša and Ranđelović, Danijela and Savić, Miroslav and Krajišnik, Danina and Milić, Jela and Savić, Snežana",
year = "2013",
abstract = "With the aid of experimental design, we developed and characterized nanoemulsions for parenteral drug delivery. Formulations containing a mixture of medium-chain triglycerides and soybean oil as oil phase, lecithin (soybean/egg) and polysorbate 80 as emulsifiers, and 0.1M phosphate buffer solution (pH 8) as aqueous phase were prepared by cold high-pressure homogenization. To study the effects of the oil content, lecithin type, and the presence of diazepam as a model drug and their interactions on physicochemical characteristics of nanoemulsions, a three factor two-level full factorial design was applied. The nanoemulsions were evaluated concerning droplet size and size distribution, surface charge, viscosity, morphology, drug-excipient interactions, and physical stability. The characterization revealed the small spherical droplets in the range 195-220nm with polydispersity index below 0.15 and zeta potential between -30 and -60mV. Interactions among the investigated factors, rather than factors alone, were shown to more profoundly affect nanoemulsion characteristics. In vivo pharmacokinetic study of selected diazepam nanoemulsions with different oil content (20%, 30%, and 40%, w/w) demonstrated fast and intense initial distribution into rat brain of diazepam from nanoemulsions with 20% and 30% (w/w) oil content, suggesting their applicability in urgent situations.",
publisher = "Wiley-Blackwell, Hoboken",
journal = "Journal of Pharmaceutical Sciences",
title = "Experimental Design in Formulation of Diazepam Nanoemulsions: Physicochemical and Pharmacokinetic Performances",
volume = "102",
number = "11",
pages = "4159-4172",
doi = "10.1002/jps.23734"
}

Đorđević, S., Radulović, T., Cekić, N., Ranđelović, D., Savić, M., Krajišnik, D., Milić, J.,& Savić, S.. (2013). Experimental Design in Formulation of Diazepam Nanoemulsions: Physicochemical and Pharmacokinetic Performances. in Journal of Pharmaceutical Sciences
Wiley-Blackwell, Hoboken., 102(11), 4159-4172.
https://doi.org/10.1002/jps.23734

Đorđević S, Radulović T, Cekić N, Ranđelović D, Savić M, Krajišnik D, Milić J, Savić S. Experimental Design in Formulation of Diazepam Nanoemulsions: Physicochemical and Pharmacokinetic Performances. in Journal of Pharmaceutical Sciences. 2013;102(11):4159-4172.
doi:10.1002/jps.23734 .

Đorđević, Sanela, Radulović, Tamara, Cekić, Nebojša, Ranđelović, Danijela, Savić, Miroslav, Krajišnik, Danina, Milić, Jela, Savić, Snežana, "Experimental Design in Formulation of Diazepam Nanoemulsions: Physicochemical and Pharmacokinetic Performances" in Journal of Pharmaceutical Sciences, 102, no. 11 (2013):4159-4172,
https://doi.org/10.1002/jps.23734 . .

TY  - CONF
AU  - Joksimović, Srđan
AU  - Obradović, Aleksandar
AU  - Timić, Tamara
AU  - Radulović, Tamara
AU  - Biawat, Poonam
AU  - Kovacević, Jovana
AU  - Milić, Marija
AU  - Batinić, Bojan
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1888
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - PWZ-029 alleviates MK-801-induced memory deficits in the rat: implications for the treatment of cognitive impairment in schizophrenia
VL  - 23
IS  - Supplement 2
SP  - S260
EP  - S260
DO  - 10.1016/S0924-977X(13)70406-1
ER  - 

@conference{
author = "Joksimović, Srđan and Obradović, Aleksandar and Timić, Tamara and Radulović, Tamara and Biawat, Poonam and Kovacević, Jovana and Milić, Marija and Batinić, Bojan and Cook, James M. and Savić, Miroslav",
year = "2013",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "PWZ-029 alleviates MK-801-induced memory deficits in the rat: implications for the treatment of cognitive impairment in schizophrenia",
volume = "23",
number = "Supplement 2",
pages = "S260-S260",
doi = "10.1016/S0924-977X(13)70406-1"
}

Joksimović, S., Obradović, A., Timić, T., Radulović, T., Biawat, P., Kovacević, J., Milić, M., Batinić, B., Cook, J. M.,& Savić, M.. (2013). PWZ-029 alleviates MK-801-induced memory deficits in the rat: implications for the treatment of cognitive impairment in schizophrenia. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 23(Supplement 2), S260-S260.
https://doi.org/10.1016/S0924-977X(13)70406-1

Joksimović S, Obradović A, Timić T, Radulović T, Biawat P, Kovacević J, Milić M, Batinić B, Cook JM, Savić M. PWZ-029 alleviates MK-801-induced memory deficits in the rat: implications for the treatment of cognitive impairment in schizophrenia. in European Neuropsychopharmacology. 2013;23(Supplement 2):S260-S260.
doi:10.1016/S0924-977X(13)70406-1 .

Joksimović, Srđan, Obradović, Aleksandar, Timić, Tamara, Radulović, Tamara, Biawat, Poonam, Kovacević, Jovana, Milić, Marija, Batinić, Bojan, Cook, James M., Savić, Miroslav, "PWZ-029 alleviates MK-801-induced memory deficits in the rat: implications for the treatment of cognitive impairment in schizophrenia" in European Neuropsychopharmacology, 23, no. Supplement 2 (2013):S260-S260,
https://doi.org/10.1016/S0924-977X(13)70406-1 . .

TY  - JOUR
AU  - Milić, Marija
AU  - Timić, Tamara
AU  - Joksimović, Srđan
AU  - Biawat, Poonam
AU  - Rallapalli, Sundari
AU  - Divljaković, Jovana
AU  - Radulović, Tamara
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1926
AB  - Inverse agonism at the benzodiazepine site of alpha(5) subunit-containing GABA(A) receptors is an attractive approach for the development of putative cognition-enhancing compounds, which are still far from clinical application. Several ligands with binding and/or functional selectivity for alpha(5) GABA(A) receptors have been synthesized and tested in a few animal models. PWZ-029 is an alpha(5) GABA(A) selective inverse agonist whose memory enhancing effects were demonstrated in the passive avoidance task in rats and in Pavlovian fear conditioning in mice. In the present study we investigated the effects of PWZ-029 administration in novel object recognition test and Morris water maze, in normal and scopolamine-treated rats. All the three doses of PWZ-029 (2,5 and 10 mg/kg) improved object recognition after the 24-h delay period, as shown by significant differences between the exploration times of the novel and old object, and the respective discrimination indices. PWZ-029 (2 mg/kg) also successfully reversed the 0.3 mg/kg scopolamine-induced deficit in recognition memory after the 1-h delay. In the Morris water maze test, PWZ-029 (5,10 and 15 mg/kg) did not significantly influence swim patterns, either during five acquisition days or during the treatment-free probe trial. PWZ-029 (2, 5 and 10 mg/kg) also proved to be ineffective in the reversal of the 1 mg/kg scopolamine-induced memory impairment in the water maze. The present mixed results encourage use of a variety of tests and experimental conditions in order to increase the predictability of preclinical testing of selective as GABA(A) inverse agonists.
PB  - Elsevier Science BV, Amsterdam
T2  - Behavioural Brain Research
T1  - PWZ-029, an inverse agonist selective for alpha(5) GABA(A) receptors, improves object recognition, but not water-maze memory in normal and scopolamine-treated rats
VL  - 241
SP  - 206
EP  - 213
DO  - 10.1016/j.bbr.2012.12.016
ER  - 

@article{
author = "Milić, Marija and Timić, Tamara and Joksimović, Srđan and Biawat, Poonam and Rallapalli, Sundari and Divljaković, Jovana and Radulović, Tamara and Cook, James M. and Savić, Miroslav",
year = "2013",
abstract = "Inverse agonism at the benzodiazepine site of alpha(5) subunit-containing GABA(A) receptors is an attractive approach for the development of putative cognition-enhancing compounds, which are still far from clinical application. Several ligands with binding and/or functional selectivity for alpha(5) GABA(A) receptors have been synthesized and tested in a few animal models. PWZ-029 is an alpha(5) GABA(A) selective inverse agonist whose memory enhancing effects were demonstrated in the passive avoidance task in rats and in Pavlovian fear conditioning in mice. In the present study we investigated the effects of PWZ-029 administration in novel object recognition test and Morris water maze, in normal and scopolamine-treated rats. All the three doses of PWZ-029 (2,5 and 10 mg/kg) improved object recognition after the 24-h delay period, as shown by significant differences between the exploration times of the novel and old object, and the respective discrimination indices. PWZ-029 (2 mg/kg) also successfully reversed the 0.3 mg/kg scopolamine-induced deficit in recognition memory after the 1-h delay. In the Morris water maze test, PWZ-029 (5,10 and 15 mg/kg) did not significantly influence swim patterns, either during five acquisition days or during the treatment-free probe trial. PWZ-029 (2, 5 and 10 mg/kg) also proved to be ineffective in the reversal of the 1 mg/kg scopolamine-induced memory impairment in the water maze. The present mixed results encourage use of a variety of tests and experimental conditions in order to increase the predictability of preclinical testing of selective as GABA(A) inverse agonists.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Behavioural Brain Research",
title = "PWZ-029, an inverse agonist selective for alpha(5) GABA(A) receptors, improves object recognition, but not water-maze memory in normal and scopolamine-treated rats",
volume = "241",
pages = "206-213",
doi = "10.1016/j.bbr.2012.12.016"
}

Milić, M., Timić, T., Joksimović, S., Biawat, P., Rallapalli, S., Divljaković, J., Radulović, T., Cook, J. M.,& Savić, M.. (2013). PWZ-029, an inverse agonist selective for alpha(5) GABA(A) receptors, improves object recognition, but not water-maze memory in normal and scopolamine-treated rats. in Behavioural Brain Research
Elsevier Science BV, Amsterdam., 241, 206-213.
https://doi.org/10.1016/j.bbr.2012.12.016

Milić M, Timić T, Joksimović S, Biawat P, Rallapalli S, Divljaković J, Radulović T, Cook JM, Savić M. PWZ-029, an inverse agonist selective for alpha(5) GABA(A) receptors, improves object recognition, but not water-maze memory in normal and scopolamine-treated rats. in Behavioural Brain Research. 2013;241:206-213.
doi:10.1016/j.bbr.2012.12.016 .

Milić, Marija, Timić, Tamara, Joksimović, Srđan, Biawat, Poonam, Rallapalli, Sundari, Divljaković, Jovana, Radulović, Tamara, Cook, James M., Savić, Miroslav, "PWZ-029, an inverse agonist selective for alpha(5) GABA(A) receptors, improves object recognition, but not water-maze memory in normal and scopolamine-treated rats" in Behavioural Brain Research, 241 (2013):206-213,
https://doi.org/10.1016/j.bbr.2012.12.016 . .

TY  - CONF
AU  - Joksimović, Srđan
AU  - Timić, Tamara
AU  - Radulović, Tamara
AU  - Rallapalli, Sundari
AU  - Milinković, Marija M.
AU  - Divljaković, Jovana
AU  - Batinić, Bojan
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2012
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1673
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - Effects of PWZ-029, an alpha(5)GABA(A) receptor inverse agonist, on scopolamine-induced spatial learning deficits in the water maze
VL  - 22
IS  - Supplement 2
SP  - S190
EP  - S191
DO  - 10.1016/S0924-977X(12)70274-2
ER  - 

@conference{
author = "Joksimović, Srđan and Timić, Tamara and Radulović, Tamara and Rallapalli, Sundari and Milinković, Marija M. and Divljaković, Jovana and Batinić, Bojan and Cook, James M. and Savić, Miroslav",
year = "2012",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Effects of PWZ-029, an alpha(5)GABA(A) receptor inverse agonist, on scopolamine-induced spatial learning deficits in the water maze",
volume = "22",
number = "Supplement 2",
pages = "S190-S191",
doi = "10.1016/S0924-977X(12)70274-2"
}

Joksimović, S., Timić, T., Radulović, T., Rallapalli, S., Milinković, M. M., Divljaković, J., Batinić, B., Cook, J. M.,& Savić, M.. (2012). Effects of PWZ-029, an alpha(5)GABA(A) receptor inverse agonist, on scopolamine-induced spatial learning deficits in the water maze. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 22(Supplement 2), S190-S191.
https://doi.org/10.1016/S0924-977X(12)70274-2

Joksimović S, Timić T, Radulović T, Rallapalli S, Milinković MM, Divljaković J, Batinić B, Cook JM, Savić M. Effects of PWZ-029, an alpha(5)GABA(A) receptor inverse agonist, on scopolamine-induced spatial learning deficits in the water maze. in European Neuropsychopharmacology. 2012;22(Supplement 2):S190-S191.
doi:10.1016/S0924-977X(12)70274-2 .

Joksimović, Srđan, Timić, Tamara, Radulović, Tamara, Rallapalli, Sundari, Milinković, Marija M., Divljaković, Jovana, Batinić, Bojan, Cook, James M., Savić, Miroslav, "Effects of PWZ-029, an alpha(5)GABA(A) receptor inverse agonist, on scopolamine-induced spatial learning deficits in the water maze" in European Neuropsychopharmacology, 22, no. Supplement 2 (2012):S190-S191,
https://doi.org/10.1016/S0924-977X(12)70274-2 . .