Drugs and receptors Flashcards
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.
Selective agonism
Potency of a range of agonists.
Selective antagonist
Competitive antagonist.
Cholinergic Receptor subtype
Two caterogories of cholinergic receptors:
mAChR - muscarine + atropine
nAChR - nicotine + curare
Histamine receptor characterisation
H1 -allergic conditions
H2 - gastric acid secretion
H3 -CNS disorders AD, obesity, pain and rhinitis.
H4 - Immune system and inflammatory conditions (rhinitis, pruritis, asthma) inflammatory pain.
Factors governing drug action
Receptor related: affinity, efficacy
Tissue-related: receptor number, signal amplification.
Affinity
Describes how well a ligand binds to the receptor.
Shown by both agonists and antagonists.
Efficacy
How well a ligand activates the receptor.
Agonists have
Affinity and efficacy
Antagonists have
Affinity but ZERO efficacy
Isoprenaline
Non-selective beta adrenoreceptor agonist, an analog of adrenaline -> relaxation of pre-contracted human bronchial rings - ASTHMA.
Beta-adrenoceptor inactivation
Bromoacetyl alprenolol menthane - irreversible antagonist - won’t come off the receptor.
Receptor reserve
Some agonists need to activate only a small fraction of existing receptors to produce the maximal system response - FULL agonist in a given tissue (can be large or small).
No receptor reserve for a partial agonist - even 100% occupancy no max response.
Signal transduction
Activation of a receptor can elicit differing responses via the signalling cascade.
Drug action is governed by
Affinity and efficacy (receptor related), receptor number and signal amplification (tissue-related).
Allosteric regulation
Binds to a different site as the agonist (binds to orthosteric site).
Inverse agonism
When a drug that binds to the same receptor as anagonistbut induces a pharmacological response opposite to that of theagonist.
Tolerance
Slow - reduction in agonist effect over time. Continuously, repeatedly, high concentrations.
Desensitisation
Rapid - uncoupled, internalised, degraded.
Specificity versus selectivity
Selectivity is better term to describe activity as no compound is ever truly specific.
Isoprenaline vs Salbutamol.
