Flashcards in Drug Targets Deck (41):
When a GPCR iis activated the affinity of its G-protein alpha subunit for GDP is decreased
The receptors for a group of signaling molecules known as growth factors are often
A) ligand-gated ion channels
C) Nuclear receptors
D) Membrane Transporters
Which RTKs have 2 polypeptide chains?
Insulin and IGF
Which of the following are chemical messengers that pass through the plasma membrane of cells and have receptor molecules in the cytoplasm?
E) Growth Hormone
Which of the following is NOT true about voltage-gated ion channels?
A) they are important in the nervous system
B) Conductance is induced by changes in membrane potential
C) they lead to changes in sodium and calcium concentrations in cells
D) they open or close in response to a NT
E) they are located on the cell membrane
D) They open or close in response to a NT
Which type of membrane proteins functions to create and maintain Na+ gradient across the cell membrane of a mammalian cell?
A) ligand-gated channel
B) voltage-gated channel
E) An ATP-powered pump
E) An ATP-powered pump
List the 5 major categories of drug targets
What is the defining feature of a transcription factor?
DNA binding domain
Where do transcription factors bind to DNA?
Bind to enhancer or promoter regions of DNA that are usually adjacent to the coding sequence of the regulated gene -> specific DNA sequence they bind to is called the response element
List the 5 classes of GPCR ligands
One category of GPCR ligands are biogenic amines. List these
One category of GPCR ligands is proteins/peptides. List these
One class of GPCR ligands is lipids. List these
Differentiate between Gs, Gi, and Gq proteins
Gs activates all isofforms of AC and Src Tyr kinase
Gi inhibits AC but activates Src Tyr kinase
Gq activates phospholipase C beta
What is the role of phosphodiesterase?
Removes cAMP, removing the signaling molecules and desensitizing the signal
Describe the steps of signal transduction involving IP3 and DAG
1. Ligand binds and Gq is freed
2. Gq activates PLC
3. PLC activates PIP2
4. PIP2 activates IP3 and DAG(in membrane)
5. IP3 releases IC Ca that binds CaM; DAG activates PKC which phosphorylates substrates
List the steps of RTK signaling
1. Ligand binds
2. Dimerization of RTKs
3. Phosphorylation oof Tyr kinase domain
4. Phosphorylation of substrate proteins
What are the major ligands for JAK-STAT receptors?
Transmit the effect of a # of hormones and cytokines -> GH, erythropoietin, leptin, interferons, IL-2-10 and 15
List the steps of JAK-STAT signaling
1. Ligand binds receptor
3. Phosphorylation of signal transducers and activation of STAT (transcription) molecules
4. STAT dimers then travel to. The nucleus where they regulate transcription
What are the 3 distinct domains of a nuclear receptor?
Ligand binding domain
Transcription activating domain
DNA binding domain
Explain how a nuclear receptor is kept static
Has an hsp90 that binds to the receptor in the absence of hormone and prevents folding into the active conformation of the receptor
Binding of a hormone ligand causes dissociation of the hsp90 stabilizer and prevents conversion too the active configuration
List the 3 types of drugs that inhibit voltage gated Na channels
Drugs used for the treatment of epilepsy
Where are L-type Ca channels located
On cardiac muscle and smooth muscle
Explain excitatory versus inhibitory NTs in terms of ion flux
Excitatory open cation channels, depolarize the cell and induce generation oof AP in excitable cells -> Ach and glutamate
Inhibitory open anion channels causing anion influx and hyperpolarization, preventing generation of APs -> GABA & glycine
Explain the structure of nicotinic Ach receptors
- ligands gated ion channel
- 5 su = 2 alpha, 1 beta, 1 gamma, 1 delta
- receptor opens a central TM ion channel when Ach binds to sites on the EC domain of its alpha su
Explain GABA-A receptors
- anionnic channels causing inward Cl- influx and hyperpolarization
- pentamericc structure similar to nicotinic Ach receptor
- GABA mediates synaptic inhibition in CNS via these channels
GABA-A receptor is a target for what 4 things?
Inhalation general anesthesia drugs
IV general anesthesia drugs
Hypnotic and anti-anxiety benzodiazepines
What type of receptor is the most common drug target?
Explain the different ways that GPCRs can be desensitized
1. GRK phosphorylates OH groups on the GPCR allowing arrestin to bind
2. Beta arrestin binds phosphorylated OH groups on GPCR desensitizing it
3. Protein phosphatase cleaves phosphates
4. Sequestration of GPCRs into endosomes then destruction of them in lysosomes
Explain Grb2 as an adaptor protein.
SH2 domain binds phosphorylated Tyr
SH3 domain binds proline rich sequences on SOS
SOS phosphorylates Ras
What are the 2 types of targeted anticancer drugs that inhibit upregulated GF signaling?
- monoclonal Abs to GF receptors and their ligands
- multikinase inhibitors
What was the major example given of a mineralocorticoid receptor antagonist?
Explain the MOA of spironolactone
1. Acts as an aldosterone receptor antagonist
2. Causes decreased Na & H2O reabsorption
3. Decreases volume of circulating blood
4. Decreases cardiac workload and bp; alleviates CHF and HTN
What is spironolactone used to treat?
HTN and CHF
Explain the broad MOA of verapamil
- it inhibits L-type Ca2 receptors
- acts on SA node causing decreased HR
- acts on AV node causing decreased AV conductivity
- acts on cardiomyocytes causing decreased contractility and O2 demand
- acts on vascular SM causing relaxation
- acts on non-vascular Sm causing muscle relaxation in the gut
What is verapamil used to treat?
Atrial and supraventricular arrhythmias
Angina pecotris (type of myocardial ischemia)
Adverse side effect = constipation
What drug specifically targets L-type Ca channels?
Explain the MOA of digoxin
Inhibits Na/K ATPase pump causing increased IC Na, which causes the Na/Ca exchanger to work harder to get rid of the excess Na in the cell, therefore causing increased Ca inside the cell and a stronger muscle contraction
Explain the wide range of effects of digoxin
- increased contractility in cardiomyocytes treating CHF
- increased contractility in GI SM causing vomiting and diarrhea
- enhanced neuronal activity leading to increased vagal activity, bradycardia and slowed AV conduction, as well as adverse side effects of disorientation, confusion and visual disturbances
- acts on AV and SA nodes causing bradycardia and slowed AV conduction
Name the drug that inhibits topoisomerase type 2