Drugs and receptors Flashcards
(43 cards)
Druggability
Describe a biological target that is known to or is predicted to bind with high affinity to a drug.
Receptor
Component of a cell that interacts with specific ligand (exogenous or endogenous) and initiates a change of biochemical events - leading to the ligands observed effects.
How do chemicals communicate?
Via receptors
What are the different types of chemicals used in signalling?
Neurotransmitters
Autocoids
Hormones
Give examples of 4 receptor types
- Ligand-gated ion channels
(nicotinic ACh receptor) - GPCR (Beta-adrenoreceptors)
- Kinase-linked receptors (GF)
- Cytosolic/nuclear receptors (steroid)
Ligand gated ion channels
Pore forming membrane proteins - allow ions to pass through.
As a result the cell undergoes a shift in electric charge distribution.
Influx of any cation or efflux of any anions.
GPCR
Largest and most diverse (7 transmembrane regions).
Targeted by >30% of drugs.
Ligands include: light energy, peptides, lipids, sugars and proteins.
G proteins
GTP to GDP and use energy from this.
Ligand binding activates them and downstream signalling.
Types of GPCR
Gs - AC and cAMP (B2-AR)
Gq - PLC IP3 and DAG increase intracellular calcium and activate PKC (M3R)
Gi - inhibit AC therefore decreases cAMP production
G0 - limited effect on alpha subunit.
Kinase-linked receptors
Kinases are enzymes that transfer phosphate groups between proteins= phosphorylation.
Phosphate is from ATP.
Transmembrane receptor - binding of ligand (EC) causes enzymatic activity on the IC side.
Nuclear receptors
Works by modifying gene transcription (oestrogen has two zinc fingers) binds to DNA.
Tamoxifen - ER modulator or partial agonist.
What can lead to pathology?
Imbalance in chemicals (allergy - increased histamine; Parkinson’s reduced dopamine) or receptors (myasthenia gravis - loss of ACh receptors; mastocytosis (increased c-kit receptor).
Why is receptor characterisation essential in a therapeutic development?
Identify the receptor involved in a pathophysiological response.
Develop drug that act at that receptor.
Quantify drug action at that receptor.
Agonist
Compound that binds to a receptor and activates it
Antagonist
A compound that reduces the effect of an antagonist
Ligand
Molecule that binds to another (usually larger) molecule.
Two state model
Describes how drugs activate receptors by inducing or supporting a conformational change in the receptor from off to on.
Potency
EC50 the concentration that gives half the maximal response.
Full agonists
Shifting of the curve (max response from lower dose). One compound is more potent.
Partial agonists
Shifts curve to the right. Lower dose is needed but it is less efficacious.
E max is the maximum response achievable.
Intrinsic activity
Or efficacy refers to the ability of a drug-receptor complex to produce a maximum functional response.
What do antagonists do?
Do not activate receptors - reverse the effects of agonists.
Competitive antagonism
Binds to the same site.
Non-competitive antagonism
Binds to allosteric, non-agonist) site on the receptor to prevent activation of the receptor.
