GABAa receptors, activation structure

Figure 11.6 Schematic representation of the GABAa receptor complex. Examples of the many structurally diverse compounds that act at different sites on the receptor (see text for details). Picrotoxinin, the active component of picrotoxin, and TBPS act as non-competitive antagonists. The barbiturates, steroids and anaesthetics are positive allosteric modulators, as are the benzodiazepine site ligands shown, with the exception of DMCM (negative allosteric modulator) and flumazenil (benzodiazepine site antagonist)...

Figure 11.9 GAB Ac receptor pharmacology and structure, (a) Various GAB Ac agonists and antagonists described in the text. Picrotoxinin is the active component of picrotoxin and also acts at GABAa receptors, (b) Presumed subunit structures of GABAc receptors. The receptors can form as homomeric assemblies of p subunits but native receptors may be heteromeric assemblies of p subunits (e.g. pi and p2) or may contain both p and y subunits...

Neuro steroids, which may be physiological modulators of brain activity, enhance GABAa receptor function 297 The three-dimensional structures of ligand-gated ion channel receptors are being modeled successfully 297 Mouse genetics reveal important functions for GABAa receptor subtypes 297... 

Hydrophobicity (log P) is related to the desolvation of the ligand, and it is assumed that the desolvation of the ligands going from water to octanol parallels that of going from water to a cleft or pocket of a receptor. Thus, log P may be an important term in establishing quantitative relationships between structure and activity (26). In order to examine the influence of the lipohilic character of the 4-PIOL analogs on the affinity for the GABAa receptor, QSAR analysis was performed (24). 

So, S.S. Kaeplus, M. Genetic neural networks for quantitative structure-activity relationships improvements and application of benzodiazepine afBnity for benzodiazepine/GABAA receptors./. Med. Chem. 1996, 39, 5246-5256. 

Dekermendjian, K. et al., Structure-activity relationships and molecular modeling analysis of flavonoids binding to the benzodiazepine site of the rat brain GABAa receptor complex, J. Med. Chem., 42, 4343, 1999. 

Zolpidem (an imidazopyridine), zale-plone (a pyrazolopyrimidine) and zopi-clone (a cyclopyrrolone) are hypnotics that, despite their different chemical structure, can bind to the benzodiazepine site on the GABAa receptor (p. 222). However, their effects do not appear to be identical to those of benzodiazepines. Thus, compared with benzodiazepines, zolpidem exerts a weaker effect on sleep phases, supposedly carries a lower risk of dependence, and appears to have less anxiolytic activity. Heterogeneity of GABAa receptors may explain these differences in activity. GABAa receptors consist of five subunits that exist in several subtypes. 

So, S.-S. and Karplus, M. (1996b). Genetic Neural Networks for Quantitative Structure-Activity Relationships Improvements and Application of Benzodiazepine Affinity for Benzodiaze-pine/GABAA Receptors. J.Med.Chem.,39,5246-5256. 

A number of compounds that have. structural characteristics broadly related to the benzodiazepines, including neuro-active flavanoids, imidazopyridines. and pyrazolopyriniid-iiKs. can act as positive mc ulators at the benzodiazepine recognition site on one or more of the GABAa receptor mbtypes. Compounds may produce all the characteristic actions of benzodiazepines or be selective, as are. for example, anxiolytic flavanoids or the. sedative-hypnotics zolpidem and zalephun. 

Fig. 22.13. Schematic representation of the y-anriinobutyric acidA (GABAa) receptor. The GABAa receptors have a pentameric structure composed predominantly of a, 3, and Y subunits arranged, in various proportions, around a central ion channel that conducts chloride. Each subunit has four membrane-spanning regions and a cysteine loop in the extracellular N-terminal domain (dashed line). The type and proportion of a and y subunit composition affects affinity, pharmacological activity, and efficacy of ligands. (Chou J. Strichartz GR, Lo EA. Pharmacology of Excitatory and Inhibitory Neurotransmission. In Golan DE, ed. Principles of Pharmacology. Philadelphia Lippincott Williams Wilkins, 2005 142 with permission.)...

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