page_title: GABAA receptor positive allosteric modulator
section_title: Barbiturates
hierarchical_section_title: GABAA receptor positive allosteric modulator / Structure-activity relationship / Barbiturates
caption_attribution_description: English: R-group position of Barbiturates
context_page_description: In pharmacology, GABAA receptor positive allosteric modulators are positive allosteric modulator molecules that increase the activity of the GABAA receptor protein in the vertebrate central nervous system.
  GABA is a major inhibitory neurotransmitter in the central nervous system. Upon binding, it triggers the GABAA receptor to open its chloride channel to allow chloride ions into the neuron, making the cell hyperpolarized and less likely to fire. GABAA PAMs increase the effect of GABA by making the channel open more frequently or for longer periods. However, they have no effect if GABA or another agonist is not present.
  Unlike GABAA receptor agonists, GABAA PAMs do not bind at the same active site as the γ-Aminobutyric acid neurotransmitter molecule: they affect the receptor by binding at a different site on the protein. This is called allosteric modulation.
  In psychopharmacology, GABAA receptor PAMs used as drugs have mainly sedative and anxiolytic effects. Examples of GABAA PAMs include alcohol, benzodiazepines such as diazepam and alprazolam, Z-drugs such as zolpidem and the barbiturate drugs.
context_section_description: Barbiturates have special uses and are organized into 4 classes: ultrashort-, short-, intermediate- and long-acting. Empirically SARs of barbiturants are based on thousands of (animal) tested compounds. They have shown that R and R´ may not be H in position 5 (see figure 8). Also, position 5 confer sedative-hypnotic properties. Generally alkyl branching in position 5 means less lipid solubility and less activity. Unsaturation show less activity in position 5 and alicyclic and aromatic rings show less potency. Polar substiuents (-NH₂, -OH, -COOH) will decrease lipid solubility but it will also eliminate activity. R´´ in position 1 is usually, H but CH₃ in that position yields less lipid solubility and duration. Exchanging S for O atom in position 2 produces thiobarbiturates, which are more lipid-soluble than the oxybarbiturates. In general, the more lipid-soluble the barbiturate, the more rapid its onset, the shorter its duration and the greater the degree of hypnotic activity. Barbiturates showed some hydrolytic problems in regard to formulation of liquid dosage forms. The difficulty is -OH catalyzed degration of the ureide rings but that can be fixed if the pH is 6 in the formulation. S(-) form of barbiturate have shown more depressant activity while the R(+) isomers have an excitatory effect.
caption: Fig 8. R-group position of Barbiturates
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