Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature
Само за регистроване кориснике
2022
Аутори
Divović Matović, BrankaKnutson, Dan
Mitrović, Jelena
Stevanović, Vladimir
Stanojević, Boban
Savić, Snežana
Cook, James M.
Savić, Miroslav M.
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
Several pyrazoloquinolinone (PQ) ligands were recently discovered as functionally selective positive modulators at the PQ site of α6-containing GABAA receptors. PQs are also neutral modulators at the benzodiazepine site. We assessed the influence of PQ compounds from three structural groups (PZ-II-029 and related deuterated analogues DK-I-56-1, RV-I-029, DK-I-60-3 and DK-I-86-1; LAU 463 and related analogues DK-I-58-1 and DK-II-58-1; and DK-I-87-1), alone and in combination with diazepam, on the behaviour of male Sprague–Dawley rats. An excellent behavioural safety profile of all tested PQs was demonstrated in the spontaneous locomotor activity, rotarod, loss of righting reflex and pentylenetetrazol tests. In interaction studies, only PZ-II-029 and its analogues prevented the ataxic effects of the benzodiazepine, as assessed in the rotarod test and during monitoring of rat locomotor activity after awakening from the loss of righting reflex. Published electrophysiological profiles of PQ... ligands imply that positive modulation elicited at α6-GABAA receptors that contain the γ2 and δ subunit, rather than their neutral modulatory action at the benzodiazepine site, may prevent the ataxic action of diazepam. Thus, PZ-II-029 and its deuterated analogues are not prone to untoward interactions with benzodiazepines and may indeed completely abolish their ataxic action, seen at therapeutic, and especially toxic concentrations.
Кључне речи:
ataxia / CNS safety / pyrazoloquinolinone binding site / pyrazoloquinolinones / α6-GABAA receptorsИзвор:
Basic & Clinical Pharmacology & Toxicology, 2022, 131, 6, 514-524Финансирање / пројекти:
- NanoCellEmoCog - Neuroimmune aspects of mood, anxiety and cognitive effects of leads/drug candidates acting at GABAA and/or sigma-2 receptors: In vitro/in vivo delineation by nano- and hiPSC-based platform (RS-7749108)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200161 (Универзитет у Београду, Фармацеутски факултет) (RS-200161)
- NIH [DA-043204 and R01NS07651]
- National Science Foundation,Division of Chemistry [CHE-1625735]
DOI: 10.1111/bcpt.13801
ISSN: 1742-7843
PubMed: 36180380
Scopus: 2-s2.0-85139451903
Колекције
Институција/група
VinčaTY - JOUR AU - Divović Matović, Branka AU - Knutson, Dan AU - Mitrović, Jelena AU - Stevanović, Vladimir AU - Stanojević, Boban AU - Savić, Snežana AU - Cook, James M. AU - Savić, Miroslav M. PY - 2022 UR - https://vinar.vin.bg.ac.rs/handle/123456789/10454 AB - Several pyrazoloquinolinone (PQ) ligands were recently discovered as functionally selective positive modulators at the PQ site of α6-containing GABAA receptors. PQs are also neutral modulators at the benzodiazepine site. We assessed the influence of PQ compounds from three structural groups (PZ-II-029 and related deuterated analogues DK-I-56-1, RV-I-029, DK-I-60-3 and DK-I-86-1; LAU 463 and related analogues DK-I-58-1 and DK-II-58-1; and DK-I-87-1), alone and in combination with diazepam, on the behaviour of male Sprague–Dawley rats. An excellent behavioural safety profile of all tested PQs was demonstrated in the spontaneous locomotor activity, rotarod, loss of righting reflex and pentylenetetrazol tests. In interaction studies, only PZ-II-029 and its analogues prevented the ataxic effects of the benzodiazepine, as assessed in the rotarod test and during monitoring of rat locomotor activity after awakening from the loss of righting reflex. Published electrophysiological profiles of PQ ligands imply that positive modulation elicited at α6-GABAA receptors that contain the γ2 and δ subunit, rather than their neutral modulatory action at the benzodiazepine site, may prevent the ataxic action of diazepam. Thus, PZ-II-029 and its deuterated analogues are not prone to untoward interactions with benzodiazepines and may indeed completely abolish their ataxic action, seen at therapeutic, and especially toxic concentrations. T2 - Basic & Clinical Pharmacology & Toxicology T1 - Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature VL - 131 IS - 6 SP - 514 EP - 524 DO - 10.1111/bcpt.13801 ER -
@article{ author = "Divović Matović, Branka and Knutson, Dan and Mitrović, Jelena and Stevanović, Vladimir and Stanojević, Boban and Savić, Snežana and Cook, James M. and Savić, Miroslav M.", year = "2022", abstract = "Several pyrazoloquinolinone (PQ) ligands were recently discovered as functionally selective positive modulators at the PQ site of α6-containing GABAA receptors. PQs are also neutral modulators at the benzodiazepine site. We assessed the influence of PQ compounds from three structural groups (PZ-II-029 and related deuterated analogues DK-I-56-1, RV-I-029, DK-I-60-3 and DK-I-86-1; LAU 463 and related analogues DK-I-58-1 and DK-II-58-1; and DK-I-87-1), alone and in combination with diazepam, on the behaviour of male Sprague–Dawley rats. An excellent behavioural safety profile of all tested PQs was demonstrated in the spontaneous locomotor activity, rotarod, loss of righting reflex and pentylenetetrazol tests. In interaction studies, only PZ-II-029 and its analogues prevented the ataxic effects of the benzodiazepine, as assessed in the rotarod test and during monitoring of rat locomotor activity after awakening from the loss of righting reflex. Published electrophysiological profiles of PQ ligands imply that positive modulation elicited at α6-GABAA receptors that contain the γ2 and δ subunit, rather than their neutral modulatory action at the benzodiazepine site, may prevent the ataxic action of diazepam. Thus, PZ-II-029 and its deuterated analogues are not prone to untoward interactions with benzodiazepines and may indeed completely abolish their ataxic action, seen at therapeutic, and especially toxic concentrations.", journal = "Basic & Clinical Pharmacology & Toxicology", title = "Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature", volume = "131", number = "6", pages = "514-524", doi = "10.1111/bcpt.13801" }
Divović Matović, B., Knutson, D., Mitrović, J., Stevanović, V., Stanojević, B., Savić, S., Cook, J. M.,& Savić, M. M.. (2022). Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature. in Basic & Clinical Pharmacology & Toxicology, 131(6), 514-524. https://doi.org/10.1111/bcpt.13801
Divović Matović B, Knutson D, Mitrović J, Stevanović V, Stanojević B, Savić S, Cook JM, Savić MM. Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature. in Basic & Clinical Pharmacology & Toxicology. 2022;131(6):514-524. doi:10.1111/bcpt.13801 .
Divović Matović, Branka, Knutson, Dan, Mitrović, Jelena, Stevanović, Vladimir, Stanojević, Boban, Savić, Snežana, Cook, James M., Savić, Miroslav M., "Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature" in Basic & Clinical Pharmacology & Toxicology, 131, no. 6 (2022):514-524, https://doi.org/10.1111/bcpt.13801 . .