L64: Drug Receptor Interaction Flashcards
Major drug target
- Enzyme
- inhibitor (mostly) / stimulator (less common)
E.g. GABA-transaminase inhibitor (Valproate) to treat seizure (insufficient GABA) - Ion channels (affect cell’s membrane potential / ionic composition)
- ligand-gated
- G-protein coupled
- Direct action
- Voltage-gated
E.g. lidocaine (Na channel blocker), cholinergic receptor, GABA receptor - Transporters
- affect PK: transport similar-in-structure drug across membrane
- affect PD: inhibit transport of endogenous compound
E.g. fluoxetine blocks serotonin transporter —> inhibits re-uptake of serotonin in synapse —> increase stimulation of post-synaptic receptor - Receptors (physiological / true drug receptor)
- Agonists
- Antagonists
E.g.
- GPCR (quick and short response)
- Nuclear receptor (soluble DNA binding protein which regulate transcription, intracellular, longer time course)
- Protein kinase (phosphorylating effector proteins in inner face of membrane, mainly on Tyrosine residue)
- Ion channels
Function and structure of receptor
Functions:
- Recognition
- Signal transduction
Structure:
- Ligand-binding domain
- Effector domain
Receptors as enzyme
e.g. Protein kinase
1. Ligand binding domain
2. Transmembrane domain
3. Protein kinase domain
—> phosphorylate effector proteins in inner face of cell membrane
Other enzyme: phosphatase, cyclase
G Protein-coupled receptor
- G-protein regulated effectors: Adenylyl cyclase, phospholipase C, Ca channel, K channel
- 7 alpha helices
- arrestin: bind to activated receptor —> trigger G-protein independent cell signalling pathway
Example mechanism
- Ligand binding —> conformational change of receptor
- Binding of G-protein to the receptor
- GDP replaced by GTP on G-protein (activated G protein)
- Activated alpha subunit + Activated beta-gamma subunit (separate)
- G-protein alpha subunit bind to adenylate cyclase (also in membrane) —> ATP converted to cAMP and releases 2 Pi
- cAMP (second messenger) activate protein kinase A —> downstream signals
- GTP slowly hydrolysed to GDP —> inactivated alpha subunit back to original position
Structure of nuclear receptor
- Carboxyl terminus
- Central: DNA binding site
- Amino terminus: regulatory
E.g. Tamoxifen binding to estrogen receptor, vitamin D receptor, retinoic acid receptor
Mechanism:
Ligand bind to receptor —> dimerise —> ligand-receptor complex bind to DNA —> regulate transcription of genes
Comparison between ligand-gated ion channels, GPCR, kinase-linked receptor, nuclear receptor
Time scale: Millisecond Second Hours Hours
Examples: Nicotinic receptor Muscarinic receptor Cytokine receptor Oestrogen receptor
Receptor regulation
- Covalent modification (allosteric vs orthosteric)
- Down-regulation / up-regulation
- By other regulatory protein
- Relocalisation
Agonist vs Inverse agonist vs Antagonist
Increase activity (+ve intrinsic activity) vs Decrease activity (-ve intrinsic activity) vs No intrinsic activity
Allosteric agonist vs Allosteric modulator
Allosteric agonist: 離遠 alter receptor site —> result in biological response Allosteric modulator (+ve/-ve): 離遠 increase action of orthosteric agonist / activator / antagonist
Spare receptor
Allow maximum drug response at less than maximum occupation of receptors despite low affinity for receptor
(Allow drug to have low affinity and still be able to achieve maximum response)
Low affinity allow rapid rate of dissociation —> quick reversal of effect
Sensitivity to low drug concentration is achieved by spare receptor capacity
Drug tolerance
Decrease in response with repeated doses
—> increase in dose is required to maintain same response
By:
- decrease in drug concentration at the receptor
- decrease in drug response by receptor
- decrease in number of receptors
Drug dependence
Altered / adaptive physiological state in which a person needs a drug to function normally through repeated administration of drug
—> withdrawal symptoms (often opposite to physiological effects of drugs)
