Receptor And Other Drug Targets Flashcards
What are the targets for drug action
Receptors
Enzymes
Ion Channels
Transporters
How do polymorphism typically affect receptors
Affect function or level of expression
Complete absence is rare
How many known polymorphism are in b2-adrenergic receptors
Coding region: 9
Upstream: 7
What is the most important polymorphism in B2R
Amino acid 16 in ligand binding domain
What b2R allele had a better response to salbutamol
2/2
Why is 2/2 better than 4/4 in salbutamol metabolism
Lower proteins expression of receptor in 4 haplotype
Do long-acting b2 agonist have an effect on response in haplotypes 2 and 4
No
Only have short acting have an effect
Why were no homozygotes for b2 adrenergic haplotypes not studied
Most people are heterozygous
Homozygous rare
Where is the most well studied polymorphism for b1-adrenoreceptors
At C-terminal end
What does the Arg form in B1-receptor show
Enhanced Gs protein interaction
Increased adenyl cyclase activation
See better response to metoprolol in homozygous
What do glycine carriers in B1-receptor polymorphisms include
Homozygous and heterozygotes
What mutations of VKORC1 cause warfarin resistance
Amino acid substitutions (rare) in vitamin K epoxide reductase
Event rare in coding region
Where are the 2 polymorphism in VKORC1
Upstream region
In first intron
Inherited together
What population has the highest frequency of VKORC1 polymorphisms
Caucasian Europeans
What is the effect of the VKORC1 polymorphism C1173T and G-1639A
C1137T affects patients warfarin dose requirement
Both form part of haplotype associated w lower warfarin dose
Why do VKCOR1 haplotypes require lower dose of warfarin
Has a low mRNA expression for VKOR
Describe warfarin resistance
Have mutations in coding regions of VKORC1
Affect warfarin binding but not vitamin K epoxide reduction
What are the 2 important amino acid substitutions that cause warfarin resistance
D36Y
V66M
What is the most common CF genetic defect
DelF508
Single phenylalanine deleted
= protein not inserted into cell membrane
Describe the CF defect G551D
Only about 5%
Channel reaches cell surface but no transport of Cl-
Gating defect = channel no longer responds to ligands
What class is the G551D defect
Class 3
What drug is prescribed for classes 3 and 4 CF
Ivacaftor
What hapolotype for B2 receptors show reduced response to salbutamol
4 in Europeans
Lower mRNA and protein expression than 2
