Benzodiazepine site ligands

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Since the allosteric potentiation of GABAa receptor function was first elucidated using BZs, this site is commonly referred to as the 'BZ site'; however, compounds of different chemical classes, 'non-BZ' ligands, have been discovered that also bind to the BZ site and produce similar therapeutic effects. These compounds provided the first evidence for heterogeneity of BZ sites and for subtypes of GABAA receptors that mediate the different pharmacological actions of BZ site ligands. Other allosteric sites present on the GABAA receptor complex include those for barbiturates, ethanol, etomidate, neurosteroids, and zinc, compounds that also modulate GABAA receptor function.103

Molecular genetics in combination with classical pharmacology have greatly facilitated understanding of how BZ site ligands interact with the GABAA receptor to produce their biological effects. The existence of 16 different GABAA subunits theoretically implies that there are many thousands of possible subunit combinations and therefore thousands of possible GABAA subtypes. However, only a limited number of subtype combinations have been found in native systems with a1b2g2, a2b3g2, and a3b3g2 being the most abundant.103 The assembly of a, b, and g subunits is required to produce functional GABAA receptors that exhibit all the pharmacological properties of native GABAA receptors. The diversity of subunits and their heterogeneous distribution between brain regions raises the question of whether GABAA receptors composed of different subunit combinations play different functional roles in the brain. GABAa receptors containing a1, a2, a3, or a5 subunits in combination with b,g subunits bind to and are potentiated by BZs. In contrast, a4- or a6-subunit-containing receptors are insensitive to classical BZs like diazepam (exceptions being the BZ antagonist, Ro15-1788 and the inverse agonist, Ro 15-4513, which show weaker activity at a4 and a6). Differences in BZ ligand affinity between a subunits results from a histidine (His 101 in rat a1) at the homologous position in a1, a2, a3, and a5, while an arginine is present in the homologous position in the a4 and a6 subunits. Transgenic mouse lines with a single histidine (H) to arginine (R) mutation at this position for individual a1, a2, a3, or a5 subunits results in an insensitivity to diazepam and other BZ ligands, while GABAA receptor expression and GABA-evoked responses remain normal.84 GABAA receptors containing a1 subunits mediate the sedative properties of diazepam as the a1 (H101R) mutant mice are resistant to the depressant effects of diazepam as measured by locomotor activity assays.104-106 GABAA receptors containing a2 subunits are proposed to play a dominant role in anxiolytic effects since a2 (H101R) mutant mice are resistant to the antianxiety effects of diazepam.105 The role of the a3-subunit-containing GABAA receptors is unclear since a3 (H126R) mutant mice respond normally to diazepam,105 although a role in anxiolytic effects has been proposed on the basis of pharmacological evidence (see Section 6.04.6.2.4). GABAA receptors containing a5 subunits are of considerable interest given their involvement in memory processes, due to their localization and proposed physiological role in the hippocampus,107 and because knockout of a5108 or H105R mutation of a5109 attenuates the effects of diazepam on memory tasks. Tolerance to the sedative effects of diazepam is absent in a5 (H105R) mice, suggesting that activation of a5-subunit-containing GABAA receptors may be important for the development of tolerance.110

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