Agonists Flashcards
Receptor Def
Molecule that a drug binds resulting in biological system change
Ligand Def
A chemical that binds to a receptor (agonist or antagonist). Can be natural/endogenous (synthesised by body eg neurotransmission) or synthetic/exogenous (eg drug)
Agonist Def
A substance that binds to a receptor to elicit a biological change
Antagonist Def
A substance that binds to a receptor eliciting no response but preventing other substances from binding
Receptor Characteristics
Structural and steric specificity (only allows specific molecule binding). Expressed only in specific tissues. Saturable and finite (at some point increasing drug conc has no biological effect due to all receptor slaready being full)
How receptors are specific
Molecules decided based on charge, size and shape
3 signaling events
reception (agonist bound recptor), transduction (transfer of signal) and response (change in system)
5 types of receptors
intracellular, extracellular, transmembrane, ligand-gated ion channels and g-protein coupled receptors
Intracellular Membrane Receptor
steroid/nuclear receptors. At cells nucleus respond to lipophilic substances to alter gene expression
Extracellular Membrane Receptor
Intrinsic Tyronise-kinase receptors (self phosphorylating), glucocorticoids receptors. Once stimulated creates signaling cascade with intermediates to alter gene expression
transmembrane receptors
jak-sat. Separate tyrosine kinase enzyme. Eg GFR receptors targeted in breast/lung cancer treatment
Ligand gated ion channels receptors
Substances bind opening an ion channel for ion flow in/out of cell eg acetylcholenic
G protein receptors
Substances bind triggering signaling cascade with secondary messengers (eg cAMP)
Example of tissue specific receptors
Angiotensin receptors on vascular smooth muscle and proximal tubule epithelium
Bmax def
The maximum amount of receptors that a drug can bind to on a tissue. y-axis of a dose binding curve
Binding Studies versus Functional Studies
Binding studies show how much the drug binds to a tissue (Bmax). Functional stusies show the magnitude of effect of amount of drug binding to tissue
Langmuir Equation Outline
Saturation kinetics. Operates under assumptions (most of which are disproven). Relationship between binding, drug conc and Kd
Langmuir Equation Assumptions
Law of mass action (drug receptor binding is infinite allowing infinite magnitude increase), binding is reversible, all receptors are equllay acessible to ligands, receptors are always free/bound and binding doesn’t alter receptor/ligand
Relationships between drug-receptor binding, drug concentration and dissociation constant
Drug receptor binding is dependent on drug conc and Kd. [RD]/[Rtotal] = [D]/([D] + Kd)
No of occupied receptors
-f = [RD]/[Rtotal)
Why are receptors not always bound to drug
Receptor desensitisation eg due to over exposure
Do receptors change shape after binding
Yes. Eg enzyme substrate complex
Is binding reversible
Sometimes but not always
Tachyphylaxis Def
Temporary desensitisation of receptors due to continuous exposure to agonist. 2 ways: receptor internalisation (ie antagonist binding to prevent agonist giving end signal to pathway) or depletion of intermediates in signaling pathway
Difference between tachyphylaxis and tolerance
Tolerance takes longer to develop and is more permanent
G-protein receptor kinass internalisation Outline
Receptor phosphorylates after agonsit binding. Phosphorylation creates receptor for arrestinB blocking further signalling. Receptor with arrestin is removed from cell surface by endosome. Receptor is dephosphorylated in endosome, losing arrestin molecule) and is either destroyed in lyssosome or retuened to celk surface
Spare Receptors Theory
On tisssues there can be more receptors present then agonist molecules. This results in hypersensitivity to agonist (as results are much faster). EC50 < Kd
Partial Agonist Outline
At full dose results in a smaller %Emax then full agonists (lower intrinsic activity). This is due to presenting both agonist and antagonist properties (resulting in agonists having ultimately less binding opportunities)
Intrinsic Activity Def
Ability to produce a response (efficacy)
Apripizole as a partial agonist
Drug for schitzophrenia. Acts as an agonist of low dopamine prosuction and acts as an antagonsit in areas where dopamine is high
How partial agonists are used in addiction
Used to wean off substances. Provides some stimulation while also slowly blocking receptors so efficacy of substance decreases in patients and lowers risks of side effects eg beueporine for morphine
