Biomaterial Database

Functional comparison of the role of gamma subunits in recombinant human gamma-aminobutyric acidA/benzodiazepine receptors. 1993

K A Wafford, and C J Bain, and P J Whiting, and J A 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.

UI	MeSH Term	Description	Entries
D006993	Hypnotics and Sedatives	Drugs used to induce drowsiness or sleep or to reduce psychological excitement or anxiety.	Hypnotic,Sedative,Sedative and Hypnotic,Sedatives,Hypnotic Effect,Hypnotic Effects,Hypnotics,Sedative Effect,Sedative Effects,Sedatives and Hypnotics,Effect, Hypnotic,Effect, Sedative,Effects, Hypnotic,Effects, Sedative,Hypnotic and Sedative
D007093	Imidazoles	Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).
D008969	Molecular Sequence Data	Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.	Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D009865	Oocytes	Female germ cells derived from OOGONIA and termed OOCYTES when they enter MEIOSIS. The primary oocytes begin meiosis but are arrested at the diplotene state until OVULATION at PUBERTY to give rise to haploid secondary oocytes or ova (OVUM).	Ovocytes,Oocyte,Ovocyte
D011725	Pyridines	Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.
D011963	Receptors, GABA-A	Cell surface proteins which bind GAMMA-AMINOBUTYRIC ACID and contain an integral membrane chloride channel. Each receptor is assembled as a pentamer from a pool of at least 19 different possible subunits. The receptors belong to a superfamily that share a common CYSTEINE loop.	Benzodiazepine-Gaba Receptors,GABA-A Receptors,Receptors, Benzodiazepine,Receptors, Benzodiazepine-GABA,Receptors, Diazepam,Receptors, GABA-Benzodiazepine,Receptors, Muscimol,Benzodiazepine Receptor,Benzodiazepine Receptors,Benzodiazepine-GABA Receptor,Diazepam Receptor,Diazepam Receptors,GABA(A) Receptor,GABA-A Receptor,GABA-A Receptor alpha Subunit,GABA-A Receptor beta Subunit,GABA-A Receptor delta Subunit,GABA-A Receptor epsilon Subunit,GABA-A Receptor gamma Subunit,GABA-A Receptor rho Subunit,GABA-Benzodiazepine Receptor,GABA-Benzodiazepine Receptors,Muscimol Receptor,Muscimol Receptors,delta Subunit, GABA-A Receptor,epsilon Subunit, GABA-A Receptor,gamma-Aminobutyric Acid Subtype A Receptors,Benzodiazepine GABA Receptor,Benzodiazepine Gaba Receptors,GABA A Receptor,GABA A Receptor alpha Subunit,GABA A Receptor beta Subunit,GABA A Receptor delta Subunit,GABA A Receptor epsilon Subunit,GABA A Receptor gamma Subunit,GABA A Receptor rho Subunit,GABA A Receptors,GABA Benzodiazepine Receptor,GABA Benzodiazepine Receptors,Receptor, Benzodiazepine,Receptor, Benzodiazepine-GABA,Receptor, Diazepam,Receptor, GABA-A,Receptor, GABA-Benzodiazepine,Receptor, Muscimol,Receptors, Benzodiazepine GABA,Receptors, GABA A,Receptors, GABA Benzodiazepine,delta Subunit, GABA A Receptor,epsilon Subunit, GABA A Receptor,gamma Aminobutyric Acid Subtype A Receptors
D011994	Recombinant Proteins	Proteins prepared by recombinant DNA technology.	Biosynthetic Protein,Biosynthetic Proteins,DNA Recombinant Proteins,Recombinant Protein,Proteins, Biosynthetic,Proteins, Recombinant DNA,DNA Proteins, Recombinant,Protein, Biosynthetic,Protein, Recombinant,Proteins, DNA Recombinant,Proteins, Recombinant,Recombinant DNA Proteins,Recombinant Proteins, DNA
D004247	DNA	A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).	DNA, Double-Stranded,Deoxyribonucleic Acid,ds-DNA,DNA, Double Stranded,Double-Stranded DNA,ds DNA
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000077334	Zolpidem	An imidazopyridine derivative and short-acting GABA-A receptor agonist that is used for the treatment of INSOMNIA.	Imidazo(1,2-a)pyridine-3-acetamide, N,N,6-trimethyl-2-(4-methylphenyl)-,Ambien,Amsic,Bikalm,Dalparan,N,N,6-Trimethyl-2-(4-methylphenyl)imidazo(1,2a)pyridine-3-acetamide hemitartrate,SL 80.0750,SL-800750-23-N,Stilnoct,Stilnox,Zodormdura,Zoldem,Zolirin,Zolpi-Lich,Zolpidem 1A Pharma,Zolpidem AbZ,Zolpidem Hemitartrate,Zolpidem Tartrate,Zolpimist,Zolpinox,SL 800750 23 N,Zolpi Lich