Articles: gaba-modulators-pharmacology.
-
Review
GABA allosteric modulators: An overview of recent developments in non-benzodiazepine modulators.
γ-Aminobutyric acid (GABA) is the major inhibitory transmitter controlling synaptic transmission and neuronal excitability. It is present in a high percentage of neurons in the central nervous system (CNS) and also present in the peripheral nervous system, and acts to maintain a balance between excitation and inhibition. GABA acts via three subclasses of receptors termed GABAA, GABAB, and GABAC. ⋯ The development of ligands for these binding sites has also led to an improved understanding of the different physiological functions and pathological processes and offers the opportunity for the development of novel therapeutics. This review focuses on the medicinal chemistry aspects including drug design, structure-activity relationships (SAR), and mechanism of actions of GABA modulators, including non-benzodiazepine ligands at the benzodiazepine binding site and modulators acting at sites other than the high-affinity benzodiazepine binding site. Recent advances in this area their future applications and potential therapeutic effects are also highlighted.
-
Advances in pharmacology · Jan 2015
ReviewAllosteric modulation of GABAA receptors via multiple drug-binding sites.
GABAA receptors are ligand-gated ion channels composed of five subunits that can be opened by GABA and be modulated by multiple pharmacologically and clinically important drugs. Over the time, hundreds of compounds from different structural classes have been demonstrated to modulate, directly activate, or inhibit GABAA receptors, and most of these compounds interact with more than one binding site at these receptors. Crystal structures of proteins and receptors homologous to GABAA receptors as well as homology modeling studies have provided insights into the possible location of ligand interaction sites. ⋯ The existence of multiple GABAA receptor subtypes with distinct subunit composition, the contribution of distinct subunit sequences to binding sites of different receptor subtypes, as well as the observation that even subunits not directly contributing to a binding site are able to influence affinity and efficacy of drugs, contribute to a unique pharmacology of each GABAA receptor subtype. Thus, each receptor subtype has to be investigated to identify a possible subtype selectivity of a compound. Although multiple binding sites make GABAA receptor pharmacology even more complicated, the exploitation of ligand interaction with novel-binding sites also offers additional possibilities for a subtype-selective modulation of GABAA receptors.
-
Pharmacol. Biochem. Behav. · Jul 2008
ReviewThe value of genetic and pharmacological approaches to understanding the complexities of GABA(A) receptor subtype functions: the anxiolytic effects of benzodiazepines.
The identification of gamma-aminobutyric acid A (GABA(A)) receptor subunit genes over the last twenty years has shown that GABA(A) receptors are made up of many different subtypes. As such the dissection of which receptor subtypes mediate which functions of clinically useful GABAergic drugs, such as benzodiazepines, has been extremely complicated. ⋯ Both have yielded exciting results, but sometimes with contradictory findings. This review highlights the strengths and weaknesses of both approaches, illustrating with specific discussion of the work, to uncover which receptor subtype(s) mediates the anxiolytic effects of benzodiazepines.
-
Substance use & misuse · Jan 2005
ReviewA brief overview of the clinical pharmacology of "club drugs".
Four different "club drugs" are reviewed: MDMA (methylenedioxymethamphetamine, "Ecstasy"), GHB (gamma-hydroxybutyrate), ketamine, and Rohypnol (flunitrazepam). The neurobiology, clinical pharmacology, and treatment issues for each are discussed.
-
Acta Anaesthesiol Scand Suppl · Jan 1995
ReviewReversal of conscious sedation by flumazenil: current status and future prospects.
Flumazenil is safe and highly effective at reversing both benzodiazepine-induced sedation and amnesia. Bolus intravenous injection is the most appropriate technique when the goal is to fully reverse conscious sedation. Currently, the proven effective dose of flumazenil is 0.5 mg. ⋯ Depression of ventilatory responsiveness induced by benzodiazepines can be reversed effectively and promptly by flumazenil. Flumazenil must be immediately available as an emergency drug in any area where benzodiazepines are used. The clinical and economic benefits of elective and routine use of flumazenil have been demonstrated, but yet to gain widespread acceptance.