drug receptors Flashcards
define druggability
- term used in drug discovery to describe a biological target such as a protein, that is known to or is predicted to bind with high affinity to a drug
- it must alter the function of the target with a therapeutic benefit to the patient
outline the drug targets.
- receptors
- enzymes
- transporters
- ion channels
What is a Receptor?
A component of a cell that interacts with a specific ligand* and initiates a change of biochemical events leading to the ligands observed effects
*Ligands can be exogenous (drugs) or endogenous (hormones, neurotransmitter, etc)
Receptors are the principal means by which chemicals communicate, what can these chemicals be?
Neurotransmitters:
- acetylcholine,
- serotonin
Autacoids:
- cytokines,
- histamine
Hormones:
- testosterone,
- hydrocortisone
name the types of receptor and the ligand which they bind.
Ligand-gated ion channels
nicotinic ACh receptor
G protein coupled receptors
beta-adrenoceptors
Kinase-linked receptors
receptors for growth factors
Cytosolic/nuclear receptors
steroid receptors
Ligand gated ion channels
Ion channelsare pore-formingmembrane proteinsthat allowionsto pass through the channel pore so that the cell undergoes a shift inelectric chargedistribution
The change in charge can be mediated by an influx of any kind ofcation(+ve) or efflux of any kind ofanion (-ve).
explanation:
- there is a ligand on the membrane which has a receptor at the end of it which collects these ions, it then causes the membrane channel to change conformity and allow the ions to pass through the channel - influx of ions
- if no ions bind to the receptor on the end of the ligand, the channel will remain closed
G-couples receptors.
- largest and most diverse group
- there are 7 transmembrane proteins that make up a complex, looping through is a transmembrane spanning domain creating a receptor embedded in the membrane
- ligand will interact with that causing a confirmational change, activating G proteins on internal side of receptor
- this releases a GDP unit on the G protein which is replaced with GTP
- this GTP activates the g-protein causing the a-unit and GDP to be released
- the a-unit interacts with their effectors causing downstream effects
Despite the fact that one G-protein coupled receptor only contains one α-subunit, this can interact with several secondary messengers, which can in turn activate multiple enzymes and catalyse many reactions. This creates a cascade response whereby one agonist binding to the GPCR can bring about the catalysis of many reactions (signal amplification).
name 2 examples of GPCRs and the pathways related to them.
- muscarinic acetylecholine receptor - coupled to the Gq protein - triggering the release of phospholipase enzyme C - this causes release of secondary messanger IP3/DAG - IP3 increases calcium release from intracellular stores, and DAG activates protein kinase C (PKC).
- beta-2-adrenergic receptor - coupled to Gs protein which activates adenylate cyclase which in turn activates protein kinase A and regulates many cellular processes
kinase-linked receptors
kinases are enzymes that catalyse phosphorylation between proteins
- ligans binds to receptor tyrosine kinase
- this activates the kinase activity within the cell
- this then catalyses the phosphorylation of tyrosines within the cell
- this causes for intracellular proteins to bind to phospho-tyrosine docking sites intracellularly which causes the propogation of signalling molecules
nuclear receptor mechanism
- these are usually found within the cytoplasm of the cell
- the ligand (steroids) diffuse through the cell and bind onto the receptor, causing a conformational change
- forms dimers
- activated nuclear receptors bind to specific dna sequences called hormone response elements
- they recruit co-factor proteins which modify chromatin structure to fascilitate transcription
- this is then translated into proteins that mediate the effacts of hormone or ligans
an imbalance of chemicals and rceeptors can lead to pathology, give an example of an imbalance and the condition it relates to for a chemical and a receptor.
Chemicals
- allergy; increased histamine
- Parkinson’s; reduced dopamine
Receptors
- myasthenia gravis; loss of ACh receptors
- Mastocytosis (Mast cells); increased c-kit receptor
outline the difference between the agonist and antagonist ligands.
Agonist
- a compound that binds to a receptor and activates it
Antagonist
- a compound that reduces the effect of an agonist
describe what is meant by the two state model of receptor activation.
describes how drugs activate receptors by inducing or supporting a conformational change in the receptor from “off” to “on”.
what is meant by efficacy (Emax) / instrinsic activity?
the maximum response achievable
- the ability of a drug-receptor complex to produce a maximum functional response
describe the types of cholinergic receptor.
-mediate the actions of acetylcholine
nicotinic:
- ligand-gated
- fast synaptic transmission
- activated by nicotine and acetylcholine
- found in neuromuscular junction - responsible for skeletal muscle contraction
- also found in autonomic ganglia, adrenal medulla and CNS
mechanism of action:
- binding of acetylcholine to nitotinic receptors opens ion channels allowing na and ca to enter and k to exit
muscarinic:
- G-protein-coupled receptors
- slower, prolongued
activated by muscarine and acetylcholine
- M1 - in CNS and autonomic ganglia
- M2 - in the heart
- M3 - in smooth muscles and glands
- M4 and M5 - in CNS
outline the agonists and antagonists of the cholinergic receptors.
nicotonic:
agonist - nicotine
antagonist - curare
muscarinic:
agonist - muscarine
antagonist - atropine
name the tissue and receptor related factors goverining drug action.
Receptor-related:
affinity
efficacy
Tissue-related:
receptor number
signal amplification
define affinity
describes how well a ligand activates the receptor
do agonists and antagonists both have affinity and efficacy?
Agonists:
Have affinity and efficacy
Antagonists:
Have affinity but zero efficacy
what is meant by an irreversible antagonist?
it wont come off the receptor
what is an allosteric ligand?
- another ligand other than the agonist and binds to a different site, creating a response
define what is meant by an inverse agonist.
When a drug that binds to the same receptor as anagonistbut induces a pharmacological response opposite to that of theagonist.
outline the differences between tolerance and desensitization.
Tolerance (slow)
reduction in agonist effect over time
continuously, repeatedly, high concentrations
Desensitization (rapid)
uncoupled
internalized
degraded
what terms can we use to describe agonists and what do they mean?
efficacy (Emax) = the concentration of a drug in which the maximum response is achieved
EC50 = concentration of a drug in which half its maximum effect is observed
potency = how strongly or efficiently a drug can produce a biological response at lower concentrations.
A more potent agonist requires a lower concentration to achieve the same effect as a less potent agonist.
intrinsic activity = the ability of a drug to activate a receptor and produce a response - scale 1-0 1 = full agonist 0-1 - partial agonist and 0 antagonist.
if a drug had a intrinsic number of 1, what would it be classified as?
full agonist
if a drug had a intrinsic number of 0, what would it be classified as?
antagonist
if a drug had a intrinsic number between 0-1, what would it be classified as?
partial agonist
what is the equation for calculating the intrinsic activity of a drug?
Emax of partial agonist / Emax of full agonist
whats the difference in potency and efficacy of a partial agonist compared to a full agonist?
partial:
- lower potency
- lower efficacy
list all the ligand types and describe how they interact differently with the receptor.
- agonist - Fully activates the receptor, producing the maximal response (Emax = 100%).
- partial agonist - Activates the receptor but produces a submaximal response (Emax < 100%).
- antagonist - Binds to the receptor but blocks activation; no intrinsic activity (Emax = 0%).
- inverse agonist - Reduces receptor’s basal (constitutive) activity, producing an opposite effect.
Outline how efficacy, affinity and potency of a compound affects the response produced
efficacy - Determines the maximum response (Emax) a drug can produce; higher efficacy = greater effect.
affinity - Reflects how strongly a drug binds to the receptor; higher affinity = stronger binding and sustained activation.
potency - Indicates the concentration (EC50) required for a response; higher potency = response achieved at lower concentrations.
name the receptors which are found in the cell membrane, cytoplasm and cell nucleus and describe the quantitative relationship between them.
cell membrane:
- GPCRS
- ion channels
- kinase-linked receptors
cytoplasm:
- steroid recpeptors
nucleus:
- nuclear receptors
Key Relationships:
Response = Receptor Occupancy: Response increases as more receptors are occupied, but saturates at maximal binding.
Spare Receptors: Full response may occur without 100% receptor occupancy due to signal amplification.
Dose-Response Curve:
Describes the relationship between drug concentration and effect (EC50 shows potency).
