page_title: GABAA receptor positive allosteric modulator
section_title: Benzodiazepines
hierarchical_section_title: GABAA receptor positive allosteric modulator / Structure-activity relationship / Benzodiazepines
caption_attribution_description: English: Different R-group analogs for neurosteroid. Groups 1-4 have significant therapeutic value.
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: According to research performed by Maddalena et al., using artificial neural networks, position 7 has the most effect on receptor affinity. When the active group in position 7 is made more lipophilic and the electronic charge is increased the receptor affinity increases. In the same study position 2´ was found to be the second-most important in affecting the affinity, but the group in that position needs to be electrophilic to have an effect. Positions 3, 6’ and 8 are of less importance. Changes to 6, 8, 9 or 4´ decrease activity. If the group in position 1 is changed to N-alkyl, haloalkyl, alkynyl and small cycle or aminoalkyl the activity is increased. Position 3 hydroxylation can cause rapid conjugation and decrease duration and potency, which can be clinically useful.
caption: Fig 10. Different R-group analogs for neurosteroids. Groups 1–4 and 10 have significant therapeutic value.
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