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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Golubeva, A. Bergmann, M. L. Frølund, B. Dalby, N. O. Simonsen, C. Cryan, J. F. Finger, B. C. Ebert, B. Hammer, H. Krogsgaard-larsen, P. Bräuner-osborne, H. Jensen, A. A. O'connor, R. M. Hoestgaard-jensen, K. Kristiansen, U. |
| Description | Author Affiliation: Hoestgaard-Jensen K ( Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.) |
| Abstract | BACKGROUND AND PURPOSE: Explorations into the heterogeneous population of native GABA type A receptors (GABAA Rs) and the physiological functions governed by the multiple GABAA R subtypes have for decades been hampered by the lack of subtype-selective ligands. EXPERIMENTAL APPROACH: The functional properties of the orthosteric GABAA receptor ligand 5-(4-piperidyl)-3-isothiazolol (Thio-4-PIOL) have been investigated in vitro, ex vivo and in vivo. KEY RESULTS: Thio-4-PIOL displayed substantial partial agonist activity at the human extrasynaptic GABAA R subtypes expressed in Xenopus oocytes, eliciting maximal responses of up to â ¼30% of that of GABA at 5 ß3 γ2S , 4 ß3 δ and 6 ß3 δ and somewhat lower efficacies at the corresponding 5 ß2 γ2S , 4 ß2 δ and 6 ß2 δ subtypes (maximal responses of 4-12%). In contrast, it was an extremely low efficacious agonist at the 1 ß3 γ2S , 1 ß2 γ2S , 2 ß2 γ2S , 2 ß3 γ2S , 3 ß2 γ2S and 3 ß3 γ2S GABAA Rs (maximal responses of 0-4%). In concordance with its agonism at extrasynaptic GABAA Rs and its de facto antagonism at the synaptic receptors, Thio-4-PIOL elicited robust tonic currents in electrophysiological recordings on slices from rat CA1 hippocampus and ventrobasal thalamus and antagonized phasic currents in hippocampal neurons. Finally, the observed effects of Thio-4-PIOL in rat tests of anxiety, locomotion, nociception and spatial memory were overall in good agreement with its in vitro and ex vivo properties. CONCLUSION AND IMPLICATIONS: The diverse signalling characteristics of Thio-4-PIOL at GABAA Rs represent one of the few examples of a functionally subtype-selective orthosteric GABAA R ligand reported to date. We propose that Thio-4-PIOL could be a useful pharmacological tool in future studies exploring the physiological roles of native synaptic and extrasynaptic GABAA Rs. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 4 |
| Volume Number | 170 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2013-10-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Brain Drug Effects GABA-A Receptor Agonists Pharmacology Piperidines Receptors, GABA Synapses Thiazoles Animals Anxiety Drug Therapy Metabolism Psychology Behavior, Animal Disease Models, Animal Dose-Response Relationship, Drug Drug Partial Agonism HEK293 Cells Ligands Membrane Potentials Memory Motor Activity Nociception Rats, Sprague-Dawley Genetics Time Factors Transfection Xenopus Laevis Comparative Study Research Support, Non-U.S. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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