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
