Lecture 2 - Drug Targets Pharmacodynamics I Flashcards
________________ are inside the cells; drugs need to be able to cross the plasma membrane to interact with them.
Intracellular Receptors
________ receptors must be ____ soluble to be able to cross the cell membrane
Intracellular; lipid
What is an example of a ligand and their mode of action?
- Steroid hormones
- The receptor binds to the ligand/hormone and has a transactivating domain or a DNA binding domain which is masked by HSP90
- As the lipid soluble hormone binds, it dissociates the chaperone and allows the bound receptor to migrate to the nucleus and bind to DNA
- This leads to transcription of genes where the hormone is bound to.
Effects of hormones on intracellular receptors are _____ and _______
slow; long-lasting
A large fraction of theraputic drugs target a family of transmemebrane receptors known as _________
G-Protein Coupled Receptors; GPCRs
At rest, the receptor is bound to a trimer of G-proteins called the ____, _______, and ______ proteins. The alpha G-protein is bound to ___ at rest. Binding of the ligand triggers change that causes ____ to be released and the alpha protein binds to __ , breaking the G-protein complex. To terminate the cycle, the alpha subunit will bind to ____ and hydrolyze it, releasing a phosphate and converting it back to _____. The system can assemble back again in its resting form.
- alpha, beta and gamma
- GDP
- GDP
- GTP
- GTP
- GDP
________ proteins that can affect the rate of which GTP is hydrolyzed by the alpha subunit.
Regulators; RGS
The beta gamma complex can ____ potassium channels and ____ cacium channels
activate; inhibit
What enzyme does the beta gamma complex affect?
PI3 kinase
What are 2 of the most common G-protein mediated signalling cascade?
- Adenylate Cyclase (AC)
- Phospholipase C (PLC)
What is the effect of receptors coupled to Gs on AC enzyme?
Gs increases the activity of AC.
What is the function of AC?
- increases the production of cAMP which activates cAMP dependent protein kinases
- therefore, an increase in AC causes the production of cAMP
What effect does Gi have on AC?
Gi inhibitd the activity of AC leading to no-less production of cAMP and less activation of protein kinase
What is the effect of Gq on PLC?
it increases the acitivty of PLC which leads to the production of inositol triphosphate (IP3) from the breakdown of PIP2.
IP3 triggers the release of ____ from the ER, which can influence a variety of signalling pathways.
Intracellular Ca2+ stores
What is the other byproduct of PIP2 breakdown which leads to the activation of protein kinase C and target substrates?
DAG, diacylglycerol
What is CaM-E?
- Calmodulim; calcium binds to calmodulin which targets proteins and activates their activity.
Protein Kinase C is a type of enzyme that will take ____ and use it as source of phosphate to transfer a phosphate to a substrate and change its activty.
ATP
How are tyrosine kinase receptors different from G-protein coupled receptors?
Tyrosine kinase don’t rely on a second set of cascading, signaling molecules that are coupled to the receptor.
Activation of TKRs is driven by _____ of receptors in the presence of a ligand, causing the receptors to ___ and become activated.
Dimerization; autophosphorylate
Which type of receptor is membrane permeable?
Intracellular receptors; steroids
Which receptor is circulating in form of drugs?
Intracellular receptor; bound to carrier globulin because of low solubility in plasma; also variable in cell surface receptors
How do intracellular receptors and cell surface reeceptors different in terms of speed of response?
- Intracellular receptors are slow as it requires DNA binding and activation of target genes
- Cell surface receptors are fast as there is rapid transduction via protein conformational change and intracellular signalling cascades.
What is the fastest mechanism of signaling in the body?
Ion channels
Ion channels allow ions to cross the plasma membrane ____, leading to changes in ______ ________
Rapidly; membrane voltage
A voltage-activated Na+ channel response (fast/slow) ____ to changes in membrane voltage. The channel sits in the _________ and have charged amino acids that are in the __________ electric field
rapidly; plasma membrane; transmembrane
____________ channels open or close in response to binding of a small signaling molecule; they also play a major role in synapses in the CNS.
Ligand-gated channels.
What is agonism?
- Refers to a substance/drug which binds to a receptor and influences its activty.
- usually depicted as a concentration-response curve.
What is EC50?
- Effective concentration 50 refers to the concentration of the drug that yield in 50% of the maximal effect.
What is Emax?
- refers to the maximal biological effect observed with the drug.
What is efficay?
refers to the maximal response you can generate with the drug (emax)
Concentrations can be plotted on a ____ scale of drug concentration or plotted on a ____ scale of drug concentration where they have a __ shape making it easier to see where the EC50 is.
linear; logarithmic; sigmodial
What is potency?
- refers to the concentration dependence
A drug with a strong potency has a ___ EC50
low
A drug with a weak potency has a ____ EC50
high
- A ___ agonist generate the maximal observed effect
- A ____ agonist can generate a fractional effective
- What cannot generte a biological effect on their own
- Which agonsits cause suppression of basal activity
- Full agonist
- partial agonist
- Antagonists
- inverse agonists
- Full agonist causes all of the receptors or the maximum number of receptors to move to the __________ form
- Partial agonists will have some balance between the 2, favoring the ____ form
- An ____won’t have any intrinsic activity on it all; it won’t change
- Inverse agonists will cause the receptors to occupy their ____ form.
- activated
- activated
- antagonist
- inhibited
