Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?
2013
Autori
Joksimović, SrđanVaragić, Zdravko
Kovacević, Jovana
van Linn, Michael
Milić, Marija
Rallapalli, Sundari
Timić, Tamara
Sieghart, Werner
Cook, James M.
Savić, Miroslav
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
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.
Ključne reči:
Recombinant receptors / Efficacy / Anxiolytic / Sedation / Ataxia / Muscle relaxation / AnticonvulsantIzvor:
QSAR & Combinatorial Science, 2013, 230, 1, 113-123Izdavač:
- Springer, New York
Finansiranje / projekti:
- 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
Institucija/grupa
PharmacyTY - 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 . .