Allosteric Drugs

• For GPCRs or LGICs, orthosteric drugs may be an alternate agonist of the receptor or a competitive inhibitor of the receptor
• For transporters, orthosteric drugs may be an alternate substrate of the transporter or a competitive blocker of the transporter
• Allosteric drugs bind to a site that is distinct from the agonist or substrate site to alter the activity of the target
• Allosteric drugs cause conformational changes in the target to alter the sensitivity of the target to its native agonist or substrate
• Allosteric drugs are not competitive inhibitors or substrates since they are not competing for the orthosteric site
• Allosteric drugs can either stimulate or reduce the activity of the target
• Allosteric drugs may have no effect on their own and require the presence of the endogenous agonist or substrate to modulate the target
• allosteric drugs may have activity on their own
• Allosteric drugs can alter the affinity or efficacy of the orthosteric agonist
• Positive allosteric modulators improve the activity of the target, leading to an enhanced effect from the orthosteric agonist
• Negative allosteric modulators reduce the activity of the target, leading to an inhibited effect, which can be complete or partial
• Silent allosteric modulators do not affect the target, but can block the binding of other allosteric drugs
• The cooperativity factor is a measure of allosterism, and its sign determines whether the allosteric drug is a positive or negative modulator
• the receptor can fluctuate between active and inactive states depending on the efficacy of the orthosteric or allosteric compound
• mAChRs are made of five subunits which all have the capacity to alter function
• Iperoxo is a high affinity agonist of mAChR, which can be stimulated by allosteric modulators
• Iperoxo has a similar structure to acetylcholine
• Positive modulator of iperoxo on mAChR:

  • Increases the efficacy of the agonist (shift to left on concentration-response curve)
  • Generates its own activity (shifts baseline up)
• The allosteric modulator stabilises the active conformation of the mAChR by locking the EC region in place
• the GABAA receptor is a member of the ligan-gated ion channel family
• The GABAA receptor is expressed throughout the CNS and mediates inhibitory neurotransmission by allowing flow of Cl-, which causes hyperpolarisation
• Benzodiazepines are allosteric modulators of the GABAA receptor
• Benzodiazepines increase the potency of the receptor activation, but does not have activity on its own since the baseline does not shift
• Benzodiazepines increase the frequency of channel opening
• GABAA receptors are heteropentamers, meaning that they contain 5 similar but non-identical subunits
• The second transmembrane domain of each subunit of the GABAA receptor forms the pore
• The positive residues of the pore allows chlorine to flow through
• In closed conformation of ion channels,

  • Residues bend towards the centre of the pore, forming a channel that is too hydrophobic and narrow for ion passage
• In opened conformation of ion channels,

  • Rotation and tilting of helices makes the channel wider and removes hydrophobicity to allow ion passage
• All GABAA receptors must contain a specific combination of subunits: Two alpha, two beta, and one other
• Subunits determine the sensitivity of the receptor to allosteric modulator
• GABA binds to the GABAA receptor in the interface between the alpha1 and beta1 subunits, which must occur in two regions for successful activation
• Diazepam binds at the interface between the alpha1 and gamma2 subunits, which enhances opening of ion channel but cannot activate the receptor since it only binds in one region