TY  - CONF
AU  - Mitrović, Jelena
AU  - Knutson, Daniel
AU  - Nikolić, Ines
AU  - Cook, James
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4285
AB  - After parenteral administration, nanoparticles interact with different proteins,
forming a shell called corona, which further influence nanoparticles’ biodistribution. Protein
adsorption is affected by particle size and shape, but also by molecular interactions of
chemical groups from the particle surface and amino-acid residues of the proteins. In human
plasma, albumin is the most abundant protein so it is frequently used for the investigation of
protein-nanoparticle interactions (1). In this study we investigated the attachment of bovine
serum albumin (BSA) to recently developed nanocrystals (2) of DK-I-56-1 (7-methoxy-2-
(4-methoxy-d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one), stabilized by
polysorbate 80 (NS2) or the combination of polysorbate 80 and poloxamer 407 (NS4).
Nanocrystal dispersion was incubated in medium containing 0.1% or 1% BSA in phosphate
buffer saline (pH 7,4) at 37 °C for 1 h. Particle size analysis was conducted by dynamic light
scattering in 10 min interval, at 37 °C on Zetasizer ZS90 (Malvern Instruments Ltd.,
Worcestershire, UK). It was shown that albumin adsorption was influenced by the
nanocrystal formulation and albumin concentration, but not incubation time. In a medium
with 0.1% BSA, no particle size difference was noticed in either formulation. However, in
case of NS2, after the addition of 1% albumin, particle size and particle size distribution
increased, which indicated albumin binding. On the other hand, in formulation NS4, with
higher albumin concentration two peaks were visible, one from the free albumin, and one
from nanocrystal particles. Therefore, it could be concluded that the affinity of albumin was
influenced mainly by the interaction with the nanocrystal stabilizers.
C3  - 8. Kongres farmaceuta Srbije; 12.-15. oktobar, Beograd, Srbija
T1  - Investigation of albumin adsorption on DK-I-56-1 nanocrystals by dynamic light scattering
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4285
ER  - 

@conference{
author = "Mitrović, Jelena and Knutson, Daniel and Nikolić, Ines and Cook, James and Savić, Miroslav and Savić, Snežana",
year = "2022",
abstract = "After parenteral administration, nanoparticles interact with different proteins,
forming a shell called corona, which further influence nanoparticles’ biodistribution. Protein
adsorption is affected by particle size and shape, but also by molecular interactions of
chemical groups from the particle surface and amino-acid residues of the proteins. In human
plasma, albumin is the most abundant protein so it is frequently used for the investigation of
protein-nanoparticle interactions (1). In this study we investigated the attachment of bovine
serum albumin (BSA) to recently developed nanocrystals (2) of DK-I-56-1 (7-methoxy-2-
(4-methoxy-d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one), stabilized by
polysorbate 80 (NS2) or the combination of polysorbate 80 and poloxamer 407 (NS4).
Nanocrystal dispersion was incubated in medium containing 0.1% or 1% BSA in phosphate
buffer saline (pH 7,4) at 37 °C for 1 h. Particle size analysis was conducted by dynamic light
scattering in 10 min interval, at 37 °C on Zetasizer ZS90 (Malvern Instruments Ltd.,
Worcestershire, UK). It was shown that albumin adsorption was influenced by the
nanocrystal formulation and albumin concentration, but not incubation time. In a medium
with 0.1% BSA, no particle size difference was noticed in either formulation. However, in
case of NS2, after the addition of 1% albumin, particle size and particle size distribution
increased, which indicated albumin binding. On the other hand, in formulation NS4, with
higher albumin concentration two peaks were visible, one from the free albumin, and one
from nanocrystal particles. Therefore, it could be concluded that the affinity of albumin was
influenced mainly by the interaction with the nanocrystal stabilizers.",
journal = "8. Kongres farmaceuta Srbije; 12.-15. oktobar, Beograd, Srbija",
title = "Investigation of albumin adsorption on DK-I-56-1 nanocrystals by dynamic light scattering",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4285"
}

Mitrović, J., Knutson, D., Nikolić, I., Cook, J., Savić, M.,& Savić, S.. (2022). Investigation of albumin adsorption on DK-I-56-1 nanocrystals by dynamic light scattering. in 8. Kongres farmaceuta Srbije; 12.-15. oktobar, Beograd, Srbija.
https://hdl.handle.net/21.15107/rcub_farfar_4285

Mitrović J, Knutson D, Nikolić I, Cook J, Savić M, Savić S. Investigation of albumin adsorption on DK-I-56-1 nanocrystals by dynamic light scattering. in 8. Kongres farmaceuta Srbije; 12.-15. oktobar, Beograd, Srbija. 2022;.
https://hdl.handle.net/21.15107/rcub_farfar_4285 .

Mitrović, Jelena, Knutson, Daniel, Nikolić, Ines, Cook, James, Savić, Miroslav, Savić, Snežana, "Investigation of albumin adsorption on DK-I-56-1 nanocrystals by dynamic light scattering" in 8. Kongres farmaceuta Srbije; 12.-15. oktobar, Beograd, Srbija (2022),
https://hdl.handle.net/21.15107/rcub_farfar_4285 .

TY  - CONF
AU  - Mitrović, Jelena
AU  - Petković, Miloš
AU  - Ranđelović, Danijela
AU  - Đoković, Jelena
AU  - Knutson, Daniel
AU  - Cook, James
AU  - Savić, Vladimir
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4097
AB  - Lipid nanoparticles are being intensively investigated for
the formulation of the drugs with poor solubility substances
(1). They represent colloid dispersions of the particles with
lipid matrix that is solid at room and body temperature.
Because of the low capacity of triglycerides for the drug
substances incorporation, alternatively, high amounts of
lecithin could be added to increase the solubilization (2).
This was used for the incorporation of DK-I-60-3 (7-
methoxy-d3-2-(4-methoxyd3-phenyl)-2,5-dihydro-
3Hpyrazolo[4,3-c]quinolin-3-one), novel deuterated
pyrazoloquinolinone ligand, with very low solubility in
water as well as in oils (3,4). However, because of
amphiphilic nature of lecithin, its localization within
nanoparticles should be analyzed, especially with respect
to stability, drug loading capacity and drug localization,
because it may additionally influence the drug release
mechanism (2).
C3  - 13th World meeting on pharmaceutics, biopharmaceutics and pharmaceutical technology, 28-31 March 2022, Rotterdam, Netherlands
T1  - Physicochemical/structural investigation of lipid nanoparticles with high lecithin amounts loaded with patent protected pyrazoloquinolinone ligand DK-I-60-3
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4097
ER  - 

@conference{
author = "Mitrović, Jelena and Petković, Miloš and Ranđelović, Danijela and Đoković, Jelena and Knutson, Daniel and Cook, James and Savić, Vladimir and Savić, Miroslav and Savić, Snežana",
year = "2022",
abstract = "Lipid nanoparticles are being intensively investigated for
the formulation of the drugs with poor solubility substances
(1). They represent colloid dispersions of the particles with
lipid matrix that is solid at room and body temperature.
Because of the low capacity of triglycerides for the drug
substances incorporation, alternatively, high amounts of
lecithin could be added to increase the solubilization (2).
This was used for the incorporation of DK-I-60-3 (7-
methoxy-d3-2-(4-methoxyd3-phenyl)-2,5-dihydro-
3Hpyrazolo[4,3-c]quinolin-3-one), novel deuterated
pyrazoloquinolinone ligand, with very low solubility in
water as well as in oils (3,4). However, because of
amphiphilic nature of lecithin, its localization within
nanoparticles should be analyzed, especially with respect
to stability, drug loading capacity and drug localization,
because it may additionally influence the drug release
mechanism (2).",
journal = "13th World meeting on pharmaceutics, biopharmaceutics and pharmaceutical technology, 28-31 March 2022, Rotterdam, Netherlands",
title = "Physicochemical/structural investigation of lipid nanoparticles with high lecithin amounts loaded with patent protected pyrazoloquinolinone ligand DK-I-60-3",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4097"
}

Mitrović, J., Petković, M., Ranđelović, D., Đoković, J., Knutson, D., Cook, J., Savić, V., Savić, M.,& Savić, S.. (2022). Physicochemical/structural investigation of lipid nanoparticles with high lecithin amounts loaded with patent protected pyrazoloquinolinone ligand DK-I-60-3. in 13th World meeting on pharmaceutics, biopharmaceutics and pharmaceutical technology, 28-31 March 2022, Rotterdam, Netherlands.
https://hdl.handle.net/21.15107/rcub_farfar_4097

Mitrović J, Petković M, Ranđelović D, Đoković J, Knutson D, Cook J, Savić V, Savić M, Savić S. Physicochemical/structural investigation of lipid nanoparticles with high lecithin amounts loaded with patent protected pyrazoloquinolinone ligand DK-I-60-3. in 13th World meeting on pharmaceutics, biopharmaceutics and pharmaceutical technology, 28-31 March 2022, Rotterdam, Netherlands. 2022;.
https://hdl.handle.net/21.15107/rcub_farfar_4097 .

Mitrović, Jelena, Petković, Miloš, Ranđelović, Danijela, Đoković, Jelena, Knutson, Daniel, Cook, James, Savić, Vladimir, Savić, Miroslav, Savić, Snežana, "Physicochemical/structural investigation of lipid nanoparticles with high lecithin amounts loaded with patent protected pyrazoloquinolinone ligand DK-I-60-3" in 13th World meeting on pharmaceutics, biopharmaceutics and pharmaceutical technology, 28-31 March 2022, Rotterdam, Netherlands (2022),
https://hdl.handle.net/21.15107/rcub_farfar_4097 .

TY  - JOUR
AU  - Mitrović, Jelena
AU  - Divović-Matović, Branka
AU  - Knutson, Daniel
AU  - Đoković, Jelena
AU  - Kremenović, Aleksandar
AU  - Dobričić, Vladimir
AU  - Ranđelović, Danijela
AU  - Pantelić, Ivana
AU  - Cook, James
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3934
AB  - Poor water solubility of new chemical entities is considered as one of the main obstacles in drug development, as it usually leads to low bioavailability after administration. To overcome these problems, the selection of the appropriate formulation technology needs to be based on the physicochemical properties of the drug and introduced in the early stages of drug research. One example of the new potential drug substance with poor solubility is DK-I-60-3, deuterated pyrazoloquinolinone, designed for the treatment of various neuropsychiatric disorders. In this research, based on preformulation studies, nanocrystal technology was chosen to improve the oral bioavailability of DK-I-60-3. Nanocrystal dispersions stabilized by sodium lauryl sulfate and polyvinylpyrrolidone were prepared by modified wet media milling technique, with the selection of appropriate process and formulation parameters. The nanoparticles characterization included particle size and zeta potential measurements, differential scanning calorimetry, X-ray powder diffraction, dissolution and solubility study, and in vivo pharmacokinetic experiments. Developed formulations had small uniform particle sizes and were stable for three months. Nanonization caused decreased crystallite size and induced crystal defects formation, as well as a DK-I-60-3 solubility increase. Furthermore, after oral administration of the developed formulations in rats, two to three-fold bioavailability enhancement was observed in plasma and investigated organs, including the brain.
PB  - MDPI AG
T2  - Pharmaceutics
T1  - Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach
VL  - 13
IS  - 8
DO  - 10.3390/pharmaceutics13081188
ER  - 

@article{
author = "Mitrović, Jelena and Divović-Matović, Branka and Knutson, Daniel and Đoković, Jelena and Kremenović, Aleksandar and Dobričić, Vladimir and Ranđelović, Danijela and Pantelić, Ivana and Cook, James and Savić, Miroslav and Savić, Snežana",
year = "2021",
abstract = "Poor water solubility of new chemical entities is considered as one of the main obstacles in drug development, as it usually leads to low bioavailability after administration. To overcome these problems, the selection of the appropriate formulation technology needs to be based on the physicochemical properties of the drug and introduced in the early stages of drug research. One example of the new potential drug substance with poor solubility is DK-I-60-3, deuterated pyrazoloquinolinone, designed for the treatment of various neuropsychiatric disorders. In this research, based on preformulation studies, nanocrystal technology was chosen to improve the oral bioavailability of DK-I-60-3. Nanocrystal dispersions stabilized by sodium lauryl sulfate and polyvinylpyrrolidone were prepared by modified wet media milling technique, with the selection of appropriate process and formulation parameters. The nanoparticles characterization included particle size and zeta potential measurements, differential scanning calorimetry, X-ray powder diffraction, dissolution and solubility study, and in vivo pharmacokinetic experiments. Developed formulations had small uniform particle sizes and were stable for three months. Nanonization caused decreased crystallite size and induced crystal defects formation, as well as a DK-I-60-3 solubility increase. Furthermore, after oral administration of the developed formulations in rats, two to three-fold bioavailability enhancement was observed in plasma and investigated organs, including the brain.",
publisher = "MDPI AG",
journal = "Pharmaceutics",
title = "Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach",
volume = "13",
number = "8",
doi = "10.3390/pharmaceutics13081188"
}

Mitrović, J., Divović-Matović, B., Knutson, D., Đoković, J., Kremenović, A., Dobričić, V., Ranđelović, D., Pantelić, I., Cook, J., Savić, M.,& Savić, S.. (2021). Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach. in Pharmaceutics
MDPI AG., 13(8).
https://doi.org/10.3390/pharmaceutics13081188

Mitrović J, Divović-Matović B, Knutson D, Đoković J, Kremenović A, Dobričić V, Ranđelović D, Pantelić I, Cook J, Savić M, Savić S. Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach. in Pharmaceutics. 2021;13(8).
doi:10.3390/pharmaceutics13081188 .

Mitrović, Jelena, Divović-Matović, Branka, Knutson, Daniel, Đoković, Jelena, Kremenović, Aleksandar, Dobričić, Vladimir, Ranđelović, Danijela, Pantelić, Ivana, Cook, James, Savić, Miroslav, Savić, Snežana, "Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach" in Pharmaceutics, 13, no. 8 (2021),
https://doi.org/10.3390/pharmaceutics13081188 . .

TY  - CONF
AU  - Mitrović, Jelena
AU  - Bjelošević, Maja
AU  - Đoković, Jelena
AU  - Ahlin Grabnar, Pegi
AU  - Planinšek, Odon
AU  - Knutson, Daniel
AU  - Cook, James
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3744
AB  - Despite of good pharmacodynamics of DK-I-56-1, novel deuterated pyrazoloquinolinones ligand, low solubility limits its administration. Nanosuspensions can help to overcome this problem, but its small particle size usually leads to particle agglomeration in short period of time. This phenomenon can be prevented by performing lyophilization. In this study cryoprotectants selection as well as characterization (particle size measurements after redispersion, scanning electron microscopy, differential scanning calorimetry and thermogravimetric measurements) of obtained freeze dried preparations was carried out. It was observed that sucrose/mannitol ratio 1:1 and 3:2 in total concentration of 10% can preserve particle size during lyophilization. However, after stability study conducted during one month storage at 25 °C and 40 °C, particle size remained in submicron range only in one sample. Changes in particle size were also followed by changes in polymorphic form of mannitol. It can be concluded that changes of crystal forms in freeze dried preparations during storage could jeopardize their stability, and therefore should be carefully examined.
T1  - Nanosuspensions of novel deuterated pyrazoloquinolinones ligand (DK-I-56-1): lyophilization procedure development through cryoprotectant selection and stability study
UR  - https://hdl.handle.net/21.15107/rcub_farfar_3744
ER  - 

@conference{
author = "Mitrović, Jelena and Bjelošević, Maja and Đoković, Jelena and Ahlin Grabnar, Pegi and Planinšek, Odon and Knutson, Daniel and Cook, James and Savić, Miroslav and Savić, Snežana",
year = "2020",
abstract = "Despite of good pharmacodynamics of DK-I-56-1, novel deuterated pyrazoloquinolinones ligand, low solubility limits its administration. Nanosuspensions can help to overcome this problem, but its small particle size usually leads to particle agglomeration in short period of time. This phenomenon can be prevented by performing lyophilization. In this study cryoprotectants selection as well as characterization (particle size measurements after redispersion, scanning electron microscopy, differential scanning calorimetry and thermogravimetric measurements) of obtained freeze dried preparations was carried out. It was observed that sucrose/mannitol ratio 1:1 and 3:2 in total concentration of 10% can preserve particle size during lyophilization. However, after stability study conducted during one month storage at 25 °C and 40 °C, particle size remained in submicron range only in one sample. Changes in particle size were also followed by changes in polymorphic form of mannitol. It can be concluded that changes of crystal forms in freeze dried preparations during storage could jeopardize their stability, and therefore should be carefully examined.",
title = "Nanosuspensions of novel deuterated pyrazoloquinolinones ligand (DK-I-56-1): lyophilization procedure development through cryoprotectant selection and stability study",
url = "https://hdl.handle.net/21.15107/rcub_farfar_3744"
}

Mitrović, J., Bjelošević, M., Đoković, J., Ahlin Grabnar, P., Planinšek, O., Knutson, D., Cook, J., Savić, M.,& Savić, S.. (2020). Nanosuspensions of novel deuterated pyrazoloquinolinones ligand (DK-I-56-1): lyophilization procedure development through cryoprotectant selection and stability study. .
https://hdl.handle.net/21.15107/rcub_farfar_3744

Mitrović J, Bjelošević M, Đoković J, Ahlin Grabnar P, Planinšek O, Knutson D, Cook J, Savić M, Savić S. Nanosuspensions of novel deuterated pyrazoloquinolinones ligand (DK-I-56-1): lyophilization procedure development through cryoprotectant selection and stability study. 2020;.
https://hdl.handle.net/21.15107/rcub_farfar_3744 .

Mitrović, Jelena, Bjelošević, Maja, Đoković, Jelena, Ahlin Grabnar, Pegi, Planinšek, Odon, Knutson, Daniel, Cook, James, Savić, Miroslav, Savić, Snežana, "Nanosuspensions of novel deuterated pyrazoloquinolinones ligand (DK-I-56-1): lyophilization procedure development through cryoprotectant selection and stability study" (2020),
https://hdl.handle.net/21.15107/rcub_farfar_3744 .

TY  - JOUR
AU  - Mitrović, Jelena
AU  - Divović, Branka
AU  - Knutson, Daniel E.
AU  - Đoković, Jelena
AU  - Vulić, Predrag
AU  - Ranđelović, Danijela
AU  - Dobričić, Vladimir
AU  - Čalija, Bojan
AU  - Cook, James M.
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3640
AB  - DK-I-56–1 (7‑methoxy‑2-(4‑methoxy‑d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one), a recently developed deuterated pyrazoloquinolinone, has been recognized as a lead candidate for treatment of various neuropsychiatric disorders. During preclinical investigation of poorly water-soluble compounds such as DK-I-56–1, the application of nanotechnology could be advantageous due to improved safety and possibly increased bioavailability of nanosized formulation. DK-I-56–1 nanosuspensions stabilized by polysorbate 80, alone or in combination with poloxamers 188 i.e. 407 or d-α-tocopheryl polyethylene glycol 1000 succinate, were prepared using a small-scale media milling device. With particle size 208.7–250.6 nm and polydispersity index <0.250, selected nanodiseprsions were stable for three weeks. Pharmacokinetic and biodistribution studies following intraperitoneal administration of three types of formulation in mice indicated high plasma DK-I-56–1 levels after solution (10,228.6 ± 1037.2 ngh/ml) and nanosuspension (6770.4 ± 770.7 ngh/ml) but not suspension administration (966.0 ± 58.1 ngh/ml). However, distribution of DK-I-56–1 after solution was heavily influenced by its composition, and brain availability of nanosuspension was superior to that of solution formulation. In spontaneous locomotor activity test, the expected hyperlocomotor effect was observed after nanosuspension administration, without compromising impact of the vehicle/excipients used. Therefore, nanonization of drug compound assembled with proper selection of stabilizers may seemingly contribute further thorough testing of DK-I-56–1 preclinical efficacy.
PB  - Elsevier B.V.
T2  - European Journal of Pharmaceutical Sciences
T1  - Nanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance
VL  - 152
DO  - 10.1016/j.ejps.2020.105432
ER  - 

@article{
author = "Mitrović, Jelena and Divović, Branka and Knutson, Daniel E. and Đoković, Jelena and Vulić, Predrag and Ranđelović, Danijela and Dobričić, Vladimir and Čalija, Bojan and Cook, James M. and Savić, Miroslav and Savić, Snežana",
year = "2020",
abstract = "DK-I-56–1 (7‑methoxy‑2-(4‑methoxy‑d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one), a recently developed deuterated pyrazoloquinolinone, has been recognized as a lead candidate for treatment of various neuropsychiatric disorders. During preclinical investigation of poorly water-soluble compounds such as DK-I-56–1, the application of nanotechnology could be advantageous due to improved safety and possibly increased bioavailability of nanosized formulation. DK-I-56–1 nanosuspensions stabilized by polysorbate 80, alone or in combination with poloxamers 188 i.e. 407 or d-α-tocopheryl polyethylene glycol 1000 succinate, were prepared using a small-scale media milling device. With particle size 208.7–250.6 nm and polydispersity index <0.250, selected nanodiseprsions were stable for three weeks. Pharmacokinetic and biodistribution studies following intraperitoneal administration of three types of formulation in mice indicated high plasma DK-I-56–1 levels after solution (10,228.6 ± 1037.2 ngh/ml) and nanosuspension (6770.4 ± 770.7 ngh/ml) but not suspension administration (966.0 ± 58.1 ngh/ml). However, distribution of DK-I-56–1 after solution was heavily influenced by its composition, and brain availability of nanosuspension was superior to that of solution formulation. In spontaneous locomotor activity test, the expected hyperlocomotor effect was observed after nanosuspension administration, without compromising impact of the vehicle/excipients used. Therefore, nanonization of drug compound assembled with proper selection of stabilizers may seemingly contribute further thorough testing of DK-I-56–1 preclinical efficacy.",
publisher = "Elsevier B.V.",
journal = "European Journal of Pharmaceutical Sciences",
title = "Nanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance",
volume = "152",
doi = "10.1016/j.ejps.2020.105432"
}

Mitrović, J., Divović, B., Knutson, D. E., Đoković, J., Vulić, P., Ranđelović, D., Dobričić, V., Čalija, B., Cook, J. M., Savić, M.,& Savić, S.. (2020). Nanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance. in European Journal of Pharmaceutical Sciences
Elsevier B.V.., 152.
https://doi.org/10.1016/j.ejps.2020.105432

Mitrović J, Divović B, Knutson DE, Đoković J, Vulić P, Ranđelović D, Dobričić V, Čalija B, Cook JM, Savić M, Savić S. Nanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance. in European Journal of Pharmaceutical Sciences. 2020;152.
doi:10.1016/j.ejps.2020.105432 .

Mitrović, Jelena, Divović, Branka, Knutson, Daniel E., Đoković, Jelena, Vulić, Predrag, Ranđelović, Danijela, Dobričić, Vladimir, Čalija, Bojan, Cook, James M., Savić, Miroslav, Savić, Snežana, "Nanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance" in European Journal of Pharmaceutical Sciences, 152 (2020),
https://doi.org/10.1016/j.ejps.2020.105432 . .

TY  - JOUR
AU  - Vasović, Dina
AU  - Divović, Branka
AU  - Treven, Marco
AU  - Knutson, Daniel
AU  - Steudle, Friederike
AU  - Scholze, Petra
AU  - Obradović, Aleksandar
AU  - Fabjan, Jure
AU  - Brković, Božidar
AU  - Sieghart, Werner
AU  - Ernst, Margot
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3315
AB  - gamma-Aminobutyric acid type A (GABA(A)) receptors containing the alpha 6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds. DK-I-56-1 at concentrations below 1 mu M enhanced gamma-aminobutyric acid (GABA) currents at recombinant rat alpha 6 beta 3 gamma 2, alpha 6 beta 3 delta and alpha 6 beta 3 receptors, whereas it was inactive at most GABA(A) receptor subtypes containing other alpha subunits. DK-I-87-1 at concentrations below 1 mu M was inactive at alpha 6-containing receptors and only weakly modulated other GABA(A) receptors investigated. Both plasma and brain tissue kinetics of DK-I-56-1 were relatively slow, with half-lives of 6 and 13 hr, respectively, enabling the persistence of estimated free brain concentrations in the range 10-300 nM throughout a 24-hr period. Results obtained in two protocols of chronic constriction injury of the infraorbital nerve in rats dosed intraperitoneally with DK-I-56-1 during 14 days after surgery or with DK-I-56-1 or DK-I-87-1 during 14 days after trigeminal neuropathy were already established, demonstrated that DK-I-56-1 but not DK-I-87-1 significantly reduced the hypersensitivity response to von Frey filaments. Significance Neuropathic pain induced by trigeminal nerve damage is poorly controlled by current treatments. DK-I-56-1 that positively modulates alpha 6 GABA(A) receptors is appropriate for repeated administration and thus may represent a novel treatment option against the development and maintenance of trigeminal neuropathic pain.
PB  - Wiley, Hoboken
T2  - European Journal of Pain
T1  - Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors
VL  - 23
IS  - 5
SP  - 973
EP  - 984
DO  - 10.1002/ejp.1365
ER  - 

@article{
author = "Vasović, Dina and Divović, Branka and Treven, Marco and Knutson, Daniel and Steudle, Friederike and Scholze, Petra and Obradović, Aleksandar and Fabjan, Jure and Brković, Božidar and Sieghart, Werner and Ernst, Margot and Cook, James M. and Savić, Miroslav",
year = "2019",
abstract = "gamma-Aminobutyric acid type A (GABA(A)) receptors containing the alpha 6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds. DK-I-56-1 at concentrations below 1 mu M enhanced gamma-aminobutyric acid (GABA) currents at recombinant rat alpha 6 beta 3 gamma 2, alpha 6 beta 3 delta and alpha 6 beta 3 receptors, whereas it was inactive at most GABA(A) receptor subtypes containing other alpha subunits. DK-I-87-1 at concentrations below 1 mu M was inactive at alpha 6-containing receptors and only weakly modulated other GABA(A) receptors investigated. Both plasma and brain tissue kinetics of DK-I-56-1 were relatively slow, with half-lives of 6 and 13 hr, respectively, enabling the persistence of estimated free brain concentrations in the range 10-300 nM throughout a 24-hr period. Results obtained in two protocols of chronic constriction injury of the infraorbital nerve in rats dosed intraperitoneally with DK-I-56-1 during 14 days after surgery or with DK-I-56-1 or DK-I-87-1 during 14 days after trigeminal neuropathy were already established, demonstrated that DK-I-56-1 but not DK-I-87-1 significantly reduced the hypersensitivity response to von Frey filaments. Significance Neuropathic pain induced by trigeminal nerve damage is poorly controlled by current treatments. DK-I-56-1 that positively modulates alpha 6 GABA(A) receptors is appropriate for repeated administration and thus may represent a novel treatment option against the development and maintenance of trigeminal neuropathic pain.",
publisher = "Wiley, Hoboken",
journal = "European Journal of Pain",
title = "Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors",
volume = "23",
number = "5",
pages = "973-984",
doi = "10.1002/ejp.1365"
}

Vasović, D., Divović, B., Treven, M., Knutson, D., Steudle, F., Scholze, P., Obradović, A., Fabjan, J., Brković, B., Sieghart, W., Ernst, M., Cook, J. M.,& Savić, M.. (2019). Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors. in European Journal of Pain
Wiley, Hoboken., 23(5), 973-984.
https://doi.org/10.1002/ejp.1365

Vasović D, Divović B, Treven M, Knutson D, Steudle F, Scholze P, Obradović A, Fabjan J, Brković B, Sieghart W, Ernst M, Cook JM, Savić M. Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors. in European Journal of Pain. 2019;23(5):973-984.
doi:10.1002/ejp.1365 .

Vasović, Dina, Divović, Branka, Treven, Marco, Knutson, Daniel, Steudle, Friederike, Scholze, Petra, Obradović, Aleksandar, Fabjan, Jure, Brković, Božidar, Sieghart, Werner, Ernst, Margot, Cook, James M., Savić, Miroslav, "Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors" in European Journal of Pain, 23, no. 5 (2019):973-984,
https://doi.org/10.1002/ejp.1365 . .

TY  - CONF
AU  - Knutson, Daniel
AU  - Kodali, Revathi
AU  - Stephen, Michael
AU  - Verma, Ranjit
AU  - Witzigmann, Christopher
AU  - Meirelles, Matheus
AU  - Zahn, Nicolas
AU  - Huber, Alec
AU  - Arnold, Leggy
AU  - Savić, Miroslav
AU  - Ernst, Margot
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3234
PB  - Amer Chemical Soc, Washington
C3  - Abstracts of Papers of the American Chemical Society
T1  - Design and synthesis of novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability
VL  - 255
UR  - https://hdl.handle.net/21.15107/rcub_farfar_3234
ER  - 

@conference{
author = "Knutson, Daniel and Kodali, Revathi and Stephen, Michael and Verma, Ranjit and Witzigmann, Christopher and Meirelles, Matheus and Zahn, Nicolas and Huber, Alec and Arnold, Leggy and Savić, Miroslav and Ernst, Margot and Sieghart, Werner and Cook, James M.",
year = "2018",
publisher = "Amer Chemical Soc, Washington",
journal = "Abstracts of Papers of the American Chemical Society",
title = "Design and synthesis of novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability",
volume = "255",
url = "https://hdl.handle.net/21.15107/rcub_farfar_3234"
}

Knutson, D., Kodali, R., Stephen, M., Verma, R., Witzigmann, C., Meirelles, M., Zahn, N., Huber, A., Arnold, L., Savić, M., Ernst, M., Sieghart, W.,& Cook, J. M.. (2018). Design and synthesis of novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability. in Abstracts of Papers of the American Chemical Society
Amer Chemical Soc, Washington., 255.
https://hdl.handle.net/21.15107/rcub_farfar_3234

Knutson D, Kodali R, Stephen M, Verma R, Witzigmann C, Meirelles M, Zahn N, Huber A, Arnold L, Savić M, Ernst M, Sieghart W, Cook JM. Design and synthesis of novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability. in Abstracts of Papers of the American Chemical Society. 2018;255.
https://hdl.handle.net/21.15107/rcub_farfar_3234 .

Knutson, Daniel, Kodali, Revathi, Stephen, Michael, Verma, Ranjit, Witzigmann, Christopher, Meirelles, Matheus, Zahn, Nicolas, Huber, Alec, Arnold, Leggy, Savić, Miroslav, Ernst, Margot, Sieghart, Werner, Cook, James M., "Design and synthesis of novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability" in Abstracts of Papers of the American Chemical Society, 255 (2018),
https://hdl.handle.net/21.15107/rcub_farfar_3234 .

TY  - JOUR
AU  - Knutson, Daniel
AU  - Kodali, Revathi
AU  - Divović, Branka
AU  - Treven, Marco
AU  - Stephen, Michael
AU  - Zahn, Nicolas
AU  - Dobričić, Vladimir
AU  - Huber, Alec
AU  - Meirelles, Matheus
AU  - Verma, Ranjit
AU  - Wimmer, Laurin
AU  - Witzigmann, Christopher
AU  - Arnold, Leggy
AU  - Chiou, Lih-Chu
AU  - Ernst, Margot
AU  - Mihovilović, Marko D.
AU  - Savić, Miroslav
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3147
AB  - Recent reports indicate that alpha 6/beta 2/3 gamma 2 GABA(A)R selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally alpha 6/beta 2/3 gamma 2 GABA(A)R selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABA(A)R a alpha 6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs and were functionally silent at diazepam sensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABA(A)R alpha 6/beta 2/3 gamma 2 subtypes.
PB  - Amer Chemical Soc, Washington
T2  - Journal of Medicinal Chemistry
T1  - Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability
VL  - 61
IS  - 6
SP  - 2422
EP  - 2446
DO  - 10.1021/acs.jmedchem.7b01664
ER  - 

@article{
author = "Knutson, Daniel and Kodali, Revathi and Divović, Branka and Treven, Marco and Stephen, Michael and Zahn, Nicolas and Dobričić, Vladimir and Huber, Alec and Meirelles, Matheus and Verma, Ranjit and Wimmer, Laurin and Witzigmann, Christopher and Arnold, Leggy and Chiou, Lih-Chu and Ernst, Margot and Mihovilović, Marko D. and Savić, Miroslav and Sieghart, Werner and Cook, James M.",
year = "2018",
abstract = "Recent reports indicate that alpha 6/beta 2/3 gamma 2 GABA(A)R selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally alpha 6/beta 2/3 gamma 2 GABA(A)R selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABA(A)R a alpha 6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs and were functionally silent at diazepam sensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABA(A)R alpha 6/beta 2/3 gamma 2 subtypes.",
publisher = "Amer Chemical Soc, Washington",
journal = "Journal of Medicinal Chemistry",
title = "Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability",
volume = "61",
number = "6",
pages = "2422-2446",
doi = "10.1021/acs.jmedchem.7b01664"
}

Knutson, D., Kodali, R., Divović, B., Treven, M., Stephen, M., Zahn, N., Dobričić, V., Huber, A., Meirelles, M., Verma, R., Wimmer, L., Witzigmann, C., Arnold, L., Chiou, L., Ernst, M., Mihovilović, M. D., Savić, M., Sieghart, W.,& Cook, J. M.. (2018). Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability. in Journal of Medicinal Chemistry
Amer Chemical Soc, Washington., 61(6), 2422-2446.
https://doi.org/10.1021/acs.jmedchem.7b01664

Knutson D, Kodali R, Divović B, Treven M, Stephen M, Zahn N, Dobričić V, Huber A, Meirelles M, Verma R, Wimmer L, Witzigmann C, Arnold L, Chiou L, Ernst M, Mihovilović MD, Savić M, Sieghart W, Cook JM. Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability. in Journal of Medicinal Chemistry. 2018;61(6):2422-2446.
doi:10.1021/acs.jmedchem.7b01664 .

Knutson, Daniel, Kodali, Revathi, Divović, Branka, Treven, Marco, Stephen, Michael, Zahn, Nicolas, Dobričić, Vladimir, Huber, Alec, Meirelles, Matheus, Verma, Ranjit, Wimmer, Laurin, Witzigmann, Christopher, Arnold, Leggy, Chiou, Lih-Chu, Ernst, Margot, Mihovilović, Marko D., Savić, Miroslav, Sieghart, Werner, Cook, James M., "Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability" in Journal of Medicinal Chemistry, 61, no. 6 (2018):2422-2446,
https://doi.org/10.1021/acs.jmedchem.7b01664 . .

TY  - CONF
AU  - Knutson, Daniel
AU  - Vasović, Dina
AU  - Divović, Branka
AU  - Treven, Marco
AU  - Steudle, Friederike
AU  - Scholze, Petra
AU  - Brković, Božidar
AU  - Sieghart, Werner
AU  - Ernst, Margot
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3052
PB  - Amer Chemical Soc, Washington
C3  - Abstracts of Papers of the American Chemical Society
T1  - Prevention of trigeminal neuropathic pain development in rats using novel deuterated GABAAR-alpha 6 subtype selective ligands
VL  - 256
UR  - https://hdl.handle.net/21.15107/rcub_farfar_3052
ER  - 

@conference{
author = "Knutson, Daniel and Vasović, Dina and Divović, Branka and Treven, Marco and Steudle, Friederike and Scholze, Petra and Brković, Božidar and Sieghart, Werner and Ernst, Margot and Cook, James M. and Savić, Miroslav",
year = "2018",
publisher = "Amer Chemical Soc, Washington",
journal = "Abstracts of Papers of the American Chemical Society",
title = "Prevention of trigeminal neuropathic pain development in rats using novel deuterated GABAAR-alpha 6 subtype selective ligands",
volume = "256",
url = "https://hdl.handle.net/21.15107/rcub_farfar_3052"
}

Knutson, D., Vasović, D., Divović, B., Treven, M., Steudle, F., Scholze, P., Brković, B., Sieghart, W., Ernst, M., Cook, J. M.,& Savić, M.. (2018). Prevention of trigeminal neuropathic pain development in rats using novel deuterated GABAAR-alpha 6 subtype selective ligands. in Abstracts of Papers of the American Chemical Society
Amer Chemical Soc, Washington., 256.
https://hdl.handle.net/21.15107/rcub_farfar_3052

Knutson D, Vasović D, Divović B, Treven M, Steudle F, Scholze P, Brković B, Sieghart W, Ernst M, Cook JM, Savić M. Prevention of trigeminal neuropathic pain development in rats using novel deuterated GABAAR-alpha 6 subtype selective ligands. in Abstracts of Papers of the American Chemical Society. 2018;256.
https://hdl.handle.net/21.15107/rcub_farfar_3052 .

Knutson, Daniel, Vasović, Dina, Divović, Branka, Treven, Marco, Steudle, Friederike, Scholze, Petra, Brković, Božidar, Sieghart, Werner, Ernst, Margot, Cook, James M., Savić, Miroslav, "Prevention of trigeminal neuropathic pain development in rats using novel deuterated GABAAR-alpha 6 subtype selective ligands" in Abstracts of Papers of the American Chemical Society, 256 (2018),
https://hdl.handle.net/21.15107/rcub_farfar_3052 .

TY  - CONF
AU  - Knutson, Daniel
AU  - Verma, Ranjit
AU  - Stephen, Michael
AU  - Kodali, Revathi
AU  - Arnold, Leggy
AU  - Savić, Miroslav
AU  - Mihovilović, Marko D.
AU  - Ernst, Margot
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2017
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2875
PB  - Amer Chemical Soc, Washington
C3  - Abstracts of Papers of the American Chemical Society
T1  - Novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability: Targeting trigeminal orofacial pain, neuropsychiatric disorders, & depression
VL  - 254
UR  - https://hdl.handle.net/21.15107/rcub_farfar_2875
ER  - 

@conference{
author = "Knutson, Daniel and Verma, Ranjit and Stephen, Michael and Kodali, Revathi and Arnold, Leggy and Savić, Miroslav and Mihovilović, Marko D. and Ernst, Margot and Sieghart, Werner and Cook, James M.",
year = "2017",
publisher = "Amer Chemical Soc, Washington",
journal = "Abstracts of Papers of the American Chemical Society",
title = "Novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability: Targeting trigeminal orofacial pain, neuropsychiatric disorders, & depression",
volume = "254",
url = "https://hdl.handle.net/21.15107/rcub_farfar_2875"
}

Knutson, D., Verma, R., Stephen, M., Kodali, R., Arnold, L., Savić, M., Mihovilović, M. D., Ernst, M., Sieghart, W.,& Cook, J. M.. (2017). Novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability: Targeting trigeminal orofacial pain, neuropsychiatric disorders, & depression. in Abstracts of Papers of the American Chemical Society
Amer Chemical Soc, Washington., 254.
https://hdl.handle.net/21.15107/rcub_farfar_2875

Knutson D, Verma R, Stephen M, Kodali R, Arnold L, Savić M, Mihovilović MD, Ernst M, Sieghart W, Cook JM. Novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability: Targeting trigeminal orofacial pain, neuropsychiatric disorders, & depression. in Abstracts of Papers of the American Chemical Society. 2017;254.
https://hdl.handle.net/21.15107/rcub_farfar_2875 .

Knutson, Daniel, Verma, Ranjit, Stephen, Michael, Kodali, Revathi, Arnold, Leggy, Savić, Miroslav, Mihovilović, Marko D., Ernst, Margot, Sieghart, Werner, Cook, James M., "Novel deuterated GABAAR-alpha 6 subtype selective ligands with improved metabolic stability and enhanced bioavailability: Targeting trigeminal orofacial pain, neuropsychiatric disorders, & depression" in Abstracts of Papers of the American Chemical Society, 254 (2017),
https://hdl.handle.net/21.15107/rcub_farfar_2875 .