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Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?

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2013
1837.pdf (427.0Kb)
Authors
Joksimović, Srđan
Varagić, Zdravko
Kovacević, Jovana
van Linn, Michael
Milić, Marija
Rallapalli, Sundari
Timić, Tamara
Sieghart, Werner
Cook, James M.
Savić, Miroslav
Article (Published version)
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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.

Keywords:
Recombinant receptors / Efficacy / Anxiolytic / Sedation / Ataxia / Muscle relaxation / Anticonvulsant
Source:
QSAR & Combinatorial Science, 2013, 230, 1, 113-123
Publisher:
  • Springer, New York
Projects:
  • Research Growth Initiative of the University of Wisconsin-Milwaukee
  • Lynde and Harry Bradley Foundation

DOI: 10.1007/s00213-013-3143-4

ISSN: 0033-3158

PubMed: 23685860

WoS: 000325700700012

Scopus: 2-s2.0-84886291954
[ Google Scholar ]
3
3
URI
http://farfar.pharmacy.bg.ac.rs/handle/123456789/1839
Collections
  • Radovi istraživača / Researchers’ publications
Institution
Pharmacy
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  - http://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",
url = "http://farfar.pharmacy.bg.ac.rs/handle/123456789/1839",
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 JM, Savić M. Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?. QSAR & Combinatorial Science. 2013;230(1):113-123
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?.
QSAR & Combinatorial ScienceSpringer, New York., 230(1), 113-123.
https://doi.org/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?" 230, no. 1 (2013):113-123,
https://doi.org/10.1007/s00213-013-3143-4 .

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