Lecture 2: Drug Targets Flashcards
T or F
When a GPCR is activated the affinity of its G-protein alpha subunit for GDP is decreased
True
The receptors for a group of signaling molecules known as GFs are often:
A) Ligand-gated ion channels
B) GPCRs
C) Nuclear receptors
D) Membrane transporters
E) Receptor tyrosine kinases
E. Receptor tyrosine kinases
What are 3 targets of targeted anticancer drugs?
1) Monoclonal antibodies to GF receptors
2) Monoclonal antibodies to ligands of GF receptors
3) Multikinase inhibitors
What is inhibited by targeted anticancer drugs?
Upregulated GF signaling
Spironolactone is what type of drug?
Used to treat what?
- Aldosterone receptor antagonist
- Tx for chronic HTN and alleviates chronic heart failure
What is the MOA of the drug Verapamil?
- Blocks L-type calcium channels = Calcium antagonist
- Used to tx atrial and supraventricular arrythmia, angina pectoris, and HTN
What is an adverse effect of Verapamil?
Constipation
What is the MOA of Digoxin?
Inhibits Na+/K+-ATPase –> enhances cardiac contractility
Which pathology is Digoxin used to treat?
CHF
What do TF’s regulate the recruitment of?
Either promote (activators) or inhibit (repressors) the recruitment of RNA polymerase to specific genes
What are 5 GPCR ligands?
1) Biogenic amines
2) Peptides/proteins
3) AAs
4) Lipids
5) Nucleotides
What are the classes of GPCRs and their functions?
- Gs: activates adenylyl cyclase and Src tyrosine kinase
- Gi: inhibits adenylyl cyclase but activates Src tyrosine kinase
- Gq: activates phospholipase C
What specific DNA sequence do TF’s bind to?
Response element
What is unique about insulin and IGF RTKs?
Contain 2 polypeptide chains, α and β, linked by disulfide bond
*Most RTKs possess a single polypeptide chain
List 5 hormones/cytokines that utilize a JAK-STAT pathway for signaling?
1) GH (somatotropin)
2) Erythropoietin
3) Leptin
4) Interferons
5) IL-2 to 10, and 15
IGF-1, VEGF, EGF, NGF, and PDGF are able to assert their actions through the use of which type of receptor?
Receptors with tyrosine kinase activity (RTK)
What is the defining feature of a TF?
Presence of the DNA-binding domain
What is unique about the effects of nuclear receptor drugs?
Effects can persist after the agonist concentraton has been reduce to zero
Describe the mechanism of a steroid hormone activating its receptor?
How is the receptor inactivated?
- In absence of hormone, hsp90 is bound and prevents folding into active conformation
- Binding of a hormone ligand (steroid) dissociates hsp90 and permits conversion to active configuration
What 3 types of drugs are inhibitors of voltage-gated Na+ channels?
1) Local anesthetics
2) Antiarrythmia drugs
3) Epilepsy drugs
Activation of a Nicotinic acetylcholine receptor induces influx of?
Causes?
- Na+
- Membrane depolarization
Nicotinic acetylcholine receptors are pentameric receptor found in what 2 locations?
1) Skeletal muscle
2) Neuronal cells
What is the differene between the actions of excitatory and inhibitory NTs in terms of channels they open?
- Excitatory (ACh and Glutamate) open cation channels –> depolarization –> APs
- Inhibitory (GABA and Glycine) open anion channels –> hyperpolarization –> prevent APs
GABA-A receptors are what type of channels and cause the influx of what?
Affects membrane potential how?
Anionic channels causing inward Cl- influx and hyperpolarization
What 4 things are GABA-A receptors a target for?
1) Inhalation anesthetics
2) IV anesthetics
3) Ethanol
4) Hypnotic and anti-anxiety benzodiazepine drugs
Propofol and neurosteroids modulate which subunit of GABA-A channels?
β subunit
Ethanol and volatile anesthetics modulate which subunit of GABA-A channels?
α subunit
Benzodiazepines modulate which subunit of GABA-A channels?
γ-subunit
Point mutations in Ras are found in 90% of what type of cancer?
Pancreatic adenocarcinomas
Point mutations in Raf are found in 70% of what type of cancers?
Melanomas
Spironolactone targets which ion channels?
Leads to?
- ENaC and Na+, K+ ATPase
- Decreases reabsorption of Na+, decreasing BP, and helps to alleviate heart failure
What is the effect of Verapamil on the SA and AV node; used therapeutically for what?
- SA node = decreased HR
- AV node = decreased AV contractility
- Tx for atrial and supra-ventricular arrhythmia
What is the effect of Verapamil on cardiomyocytes; used therapeutically for what?
- Decreased contractility and O2 demand
- Tx for Angina pectoris
What is the effect of Verapamil on vascular smooth muscle; used therapeutically for what?
- Vascular smooth muscle relaxation
- Tx for HTN
What is the effect of Digoxin on GI smooth muscle, brain nuclei and the SA and AV nodes?
Producing what side effects?
- GI smooth muscle: increased contractility –> vomiting and diarrhea
- Brain nuclei: enhanced neuronal activity and increased vagal activity –> vomiting, diarrhea, disorientation, confusion, visual disturbances, bradycardia, and slowed AV conductivity
- SA and AV node: bradycardia and slowed AV conductivity
What is the MOA of Etoposide?
Topoisomerase type II inhibitor –> DNA damage –> induction of p53 –> triggers apoptosis of cancer cells
How does Etoposide work?
What are its therapeutic uses?
- Causes DNA damage as a topoisomerase inhibitor leading to activation of p53
- p53 induces expression of proteins causing release of proapoptotic proteins from mitochondria into cytosol
- These proteins activate caspases to trigger apoptosis of a cancer cell
What do SH2 and SH3 bind to, respectively
SH2: tyrosine kinases
SH3: proline rich
What is SOS?
Actvates?
- Encodes guanine nucleotide exchange factor
- Activates Ras
