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KA Wafford, CJ Bain, PJ Whiting and JA Kemp
Neuroscience Research Centre, Merck, Sharp & Dohme Research Laboratories, Harlow, Essex, UK.
The effect of benzodiazepines on the activity of gamma-aminobutyric acid (GABA)A receptors has been shown to be influenced by different alpha subunits and can also be affected by the presence of different gamma subunits. Previous studies have shown that receptors without a gamma subunit or those containing gamma 1 are modulated to a lesser degree by benzodiazepines. Using the Xenopus oocyte expression system to express different subunit combinations, a detailed analysis of the pharmacological modulation of GABAA receptors by various benzodiazepine site ligands has been carried out. We analyzed 14 compounds, varying through full agonist, partial agonist, antagonist, and inverse agonist, with receptors consisting of alpha 2 beta 1, alpha 2 beta 1 gamma 2S, and alpha 2 beta 1 gamma 1 and we demonstrate differences in their extent of potentiation by different benzodiazepine-type ligands. Most compounds showed negligible effects on alpha 2 beta 1 and most agonists, particularly the imidazopyridines zolpidem, alpidem, and AHR14,749, exhibited less potentiation with alpha 2 beta 1 gamma 1 than with alpha 2 beta 1 gamma 2S. The inverse agonists dimethoxy-4-ethyl- beta-carboline-3-carboxylate and Ro15-4513 did not act as inverse agonists and produced slight potentiation of alpha 2 beta 1 gamma 1 receptors. Concentration-response curves were constructed for five selected agonists to evaluate both affinity and efficacy differences between alpha 2 beta 1 gamma 2 and alpha 2 beta 1 gamma 1 receptors. Most compounds showed lower efficacy and up to 10-fold lower affinity with alpha 2 beta 1 gamma 1. Zolpidem showed slightly higher affinity but an extremely low efficacy; FG8205 also showed a markedly lower efficacy and was the most selective compound for alpha 2 beta 1 gamma 2S versus alpha 2 beta 1 gamma 1 receptors. CL218,872 showed high efficacy with alpha 2 beta 1 gamma 1 and affinity similar to that with alpha 2 beta 1 gamma 2 (being the least selective compound), suggesting that some low efficacy partial agonists with gamma 2-containing receptors may be more efficacious with gamma 1-containing receptors. The antagonists Ro15-1788 and CGS8216, although they blocked flunitrazepam potentiation of alpha 2 beta 1 gamma 2, could not block potentiation of alpha 2 beta 1 gamma 1. This study demonstrates that unique pharmacological profiles can be conferred by receptors containing different gamma subunits.
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