Term
| Many drug targets are protein receptors. What are some other examples of viable drug targets? |
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Definition
1) Enzymes (Statins target HMG CoA reductase)
2) Transport Proteins (Digoxin and Oubain for Na/K ATPase)
3) Structural Proteins (Taxol- anti-cancer binds tubulin and promotes polymerization)
4) Nucleic Acids (Cisplatin treats cancer by binding DNA) |
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Term
| What types of interactions dominate Receptor-Ligand interactions? |
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Definition
Weak (H-bonding, electrostatic, van der waals).
Note- sometimes irreversible, covalent, inhibitory interactions can occur- phenoxybenzamine for adrenal tumors |
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Term
| Why are some receptors called "orphan" receptors? |
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Definition
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Term
| How are receptors generally classified? |
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Definition
1) Ligand-general (e.g. amino acid)
2) Ligand-specific (e.g. glycine)
3) Genetic (sequence homology designation)
4) Downstream signaling |
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Term
| What types of receptors are Nicotinic AcR and GABA receptors? |
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Definition
Ligand-gated ion channels.
Rapid and short lasting! |
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Term
| What types of receptors are steroid hormone, thyroid hormone and retinoid receptors? |
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Definition
| Transcription Factor- DNA binding and transcriptional regulation |
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Term
Provide an example of how each of the following receptors can act as and enzyme.
1) Tyrosine Kinase
2) Serine/Threonine Kinase
3) Protein Tyrosine Phosphatase
4) Guanylyl Cyclase |
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Definition
1) Receptor-encoded (insulin receptor) or associated (cytokine receptor)
2) TGF-b family
3) axon guidance using cell adhesion molecules as ligands
4) produces cGMP from GTP, which regulates blood volume and blood pressure when bound by atrial natriuretic peptide |
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Term
| What are the basic assumptions of AJ Clark's Receptor Theory? |
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Definition
1) L and R interaction is reversible
2) All receptors for given ligand Equivalent and Independent
3) Response proportional to # occupied receptors
4) Ligand is only is state A (free) or B (ligand-bound) |
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Term
1) What does it mean when [ligand] = Kd?
2) How does one increase saturation from almost zero (fb=0.1) to almost maximal (fb= 0.9)? |
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Definition
1) When there is half-saturation of reversible ligand binding to a receptor
2) 2 orders of magnitude increase in [ligand], irrespective of receptor affinity. |
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Term
| When can Clark's receptor-ligand model be applied to ligand effects on a biological response? |
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Definition
1) Magnitude of response is proportional to amount of receptors bound
2) Maximum biological respose occurs when all receptors are bound
3) Binding of ligand to receptor does not exhibit cooperativity.
If these are true, the fractional biological effect (Fe) is equal to the fractional occupancy of receptors (Fb) or
Fe= [L]/ [L] + Kd = [RL]/[Rtotal] = Fb |
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Term
| When do you use ED50 vs. EC50 |
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Definition
EC50 refers to actual concentration of ligand where 50% of maximal receptor occupancy is achieved.
If exact concentration is not know (common in vivo), use ED50 (dose) |
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Term
| Why plot a dose response curve with the Log ligand dose? |
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Definition
| It creates a sigmoid curve, where the lower dose values are expanded, so that you can narrow down the region where maximum change per increase in dose is achieved. |
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Term
| How is it that some cells generate maximal biological responses at lower ligand concentrations than are required to generate total receptor occupancy? |
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Definition
Spare Receptors!
This can either be because one activated receptor interacts with many effectors or because the lifetime of an "active" effector many be longer than that of the receptor/ligand complex.
Appear as "left" shift in DR curve
[L]< Kd |
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Term
| How is Albuterol an example of "spare-receptor" kinetics? |
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Definition
B2-selective adrenergic receptor agonist used to treat asthma and COPD (bronchodilator).
It only occupies its receptor for a period of ms, but downstream G protein effector is activated by 100s of ms. |
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Term
| Why is cooperativity an example of a "deviation from classical ligand-receptor behavior"? Provide an example |
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Definition
DR curve is broader and steeper, because of multiple binding sites for a single ligand, which are NOT independent.
If hyperbolic DR curve is steeper, cooperation is (+), if flatter, it is (-)
Ex) Hb is (+) |
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Term
True:False
1) Competitive Antagonists alter maximal drug response but not drug potency.
2) Noncompetitive Antagonists alter drug potency, but not maximal responsiveness |
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Definition
1) False! They alter drug potency (often EC50), not maximal response, producing a right-shift in the DR curve
2) False!- the opposite is true.
Relate back to Vmax and Km. Remember, competitive altered Km, but not Vmax (similar to EC50 and not ECmax)
Competitive= potency
Noncompetitive= maximal activity. |
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Term
| How is aripiperazole used to treat Schizophrenia? |
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Definition
It is a partial agonist of D2 dopamine receptors. Remember, partial agonists can act as antagonists in the presence of a full agonist.
In this case, the dopamine system is overactive, so aripiperazole acts as an antagonist. |
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Term
| What are inverse agonists? How can they be problematic? |
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Definition
Bind and stabilize "inactive confirmation."
Used to block constitutively active receptors. Can get problematic with downstream signaling, however.
Ex) if cells are over-expressing B2 adrenergic receptor, propananol can act as an inverse agonist by blocking downstream effectors that trigger cAMP production, but activate others that are coupled to MAPK-mediated pathways. |
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