Agonists and antagonists Flashcards
Ways of regulating cell function
- altered membrane potential
- altered enzyme activity
- altered gene expression
Effects of drugs
- agonism; produces effects
- antagonism; blocks effects
- densensitisation; reduces effects
The patch clamp technique
A method of measuring the activity of a single ionotropic receptor. Uses an electrode within a micropipette to measure the response as a quantifiable current.
Inverse agonists
Have negative efficacy, as they reduce spontaneous opening of ion channels.
Super-agonists
Highly efficacious agonists that can produce a maximal response from the cell without binding to all of the available receptors. Emax is above 100%.
Spare receptors
Receptors that are free/unbound after a maximal response has been produced by a super-agonist.
Partial agonists
Low efficacy agonists that cannot produce the cell’s maximal response, even when they have bound to all of the available receptors.
Types of antagonist
- competitive antagonist
- irreversible antagonist
- allosteric/ non-competitive antagonist
- channel blockers
- physiological antagonist
Competitive antagonists
Bind reversibly at the same site as the agonist, producing a parallel shift to the right of agonist/dose response curves. The initial response to the agonist is reduced, but with increasing agonist concentration the maximal response can eventually be reached.
Irreversible antagonists
Bind irreversibly by forming a covalent bond or binding very tightly at the same site as the agonist, decreasing the maximal response. Newly classified as protein degradation inducers.
Allosteric antagonists
Bind reversibly at a distinct site from the agonist, decreasing agonist affinity and reducing the likelihood of agonist binding.
Channel blockers
Bind inside the channel and prevent the passage of ions. Binding tends to be enhanced by receptor activation.
Physiological antagonists
Antagonise the physiological effect of some agonists, but via a different mechanism.
Desensitisation
The prolonged or repeated exposure to an agonist reduces the response to that drug. Mechanisms include up-regulation of the receptor, or up-regulation of the degrading enzyme for the respective drug.
Receptor classification
Receptors are named according to the transmitter or hormone with which they interact. Most hormones interact with more than one type of receptor, and differences in protein structure underlie differences between subtypes.
Receptor super-families
- integral ion channels eg. nicotinic receptor, glycine receptor
- integral tyrosine kinases eg. insulin receptor
- steroid receptors/nuclear receptors eg. estrogen receptor, androgen receptor
- G-protein coupled receptors
- cytokine receptors
Allosteric effects on GABAa receptor
GABAa receptors are ligand-gated chloride channels found in the brain. Benzodiazepine agonists bind and increase the affinity of the GABA binding site, thereby increasing channel opening leading to a Cl- influx.
Steroid/nuclear receptors
- act in the nucleus, but are most often located in the cytoplasm
- contain a ligand binding domain (LBD), which functions like a folding sensor; folded with steroid, unfolded without
- contain a DNA binding domain (DBD), which mediates binding to the genome
- contain a response element (RE)
G-protein coupled receptors
- comprised of 7 transmembrane helices associated with proteins
- homo or hetero dimers
- many GPCRs (~4% of genome)
- several G subunits (Gs, Gi, Gq)
Cytokine receptors
Similar to tyrosine kinase receptors, but only have a long peptide intracellularly.
