P3 - Receptors as Drug Targets Flashcards
What kind of binding is involved in ligand-receptor binding, and why?
Non-covalent
Because you need to be able to turn the signal on and off
The substrate does NOT react with the receptor, just causes a conformational change
What are the 3 types of drugs that bind receptors and what effect does each have?
Agonist: Same response as endogenous substrate
Antagonist: Causes no response, just prevents substrate from binding
Inverse Agonist: Antagonistic effects but also eliminates any resting activity
Give an example of an endogenous substrate that binds an ion channel receptor
Acetylcholine
Binds nicotinic Ach receptor in neuromuscular junctions
How is Ach formed?
Acetyl-CoA from mitochondria + Choline taken up from the synaptic cleft
Name a class of drugs that antagonise an ion channel receptor and give two examples
Neuromuscular blockers (used during surgery) block the nAchR in neuromuscular junctions
Tubocurarine
Pancuronium (more modern analogue)
Give some examples of endogenous substrates that bind GPCRs
Glutamate binds mGluRs GABA binds the GABAb receptor Adrenaline binds alpha1-2 and beta 1-3 receptors Ach binds mAchRs M1-M5 Serotonin
What are the effects of adrenaline binding its receptors?
a1: constriction of vascular and visceral smooth muscle
a2: vasoconstriction
b1: increased heart rate
b2: bronchodilation
b3: bladder detrusor relaxation
Name an antagonist of a GPCR
Propranolol is a beta adrenergic receptor antagonist. Also known as ‘beta blocker’. Competes with adrenaline for b1. Used to reduce heart rate and therefore BP
Give an example of an endogenous substrate that binds a kinase linked receptor
Epidermal growth factor binds to EGFR.
Why are kinase linked receptors often used as the target for anticancer drugs and how can they be targeted?
Bind growth factors, often overexpressed or mutated in many cancers, leading to uncontrolled cell proliferation.
Has ATP binding site (as phosphorylation requires ATP) so inhibits can bind ligand site or ATP binding site.
Name an antagonist of a kinase linked receptor
Gefitinib (anti cancer drug) is an antagonist of the EGFR
Give an example of an endogenous substrate of a nuclear receptor
Steroid hormones (oestrogen, testosterone, progesterone), thyroid hormones, retinoids
Give an example of an antagonist of a nuclear receptor
Tamoxifen is a breast cancer drug and antagonist of the oestrogen receptor
Prevents growth and proliferation caused by oestrogen
What is receptor desensitisation?
If an agonist binds too strongly to a receptor, it begins to act like an antagonist as it prevents the receptor from being activated again. Same effect is caused by constant exposure to a high concentration of agonist.
This may cause the receptor-agonist complex to be exocytosed from the membrane.
What causes tolerance and dependence to a drug?
Sufficient exposure to an antagonist causes a cell to synthesise more receptors to compensate. Cell becomes more sensitive to natural substrate. Dose of antagonist required to achieve same effect is increased. Removal of the drug whilst there is this extra sensitivity to the natural substrate causes withdrawal symptoms.
