Molecular Basis of Drug Action

Question 1

(1) Describe nonspecific drug action and give examples.

Answer 1

drugs that are biochemically different but act by the same physiochemical process (ie. laxatives are surfactants or different bases uses to treat acid reflux); note biological activity occurs at high concentrations and slight changes in chemical structure do not markedly affect biological activity

Question 2

(1) Describe specific drug action and give examples.

Answer 2

drugs that act on a specific target site, similar chemical structures produce similar biological effects but slight modifications markedly alter biological activity, action occurs at low concentrations (ie. epinephrine is a non specific adrenergic actor while phenylephrine is specific to a1 receptors

Question 3

(2) Name the four major receptor classes.

Answer 3

cytosolic receptors (often nuclear);
ligand activated enzymes;
ligand activated ion channels;
G protein coupled receptors

Question 4

(2) Describe the mechanism of a cytosolic receptor.

Answer 4

1. ligand binding
   2, DNA binding domain is freed
2. transcription activating domain causes creation of cellular product

Question 5

(2) Describe the action of ligand regulated receptor using the example of a tyrosine kinase.

Answer 5

1. receptors dimerize
2. phosphorylation of tyrosine residues
3. tyrosine residues can in turn phosphorylate another substrate

Question 6

(2) Describe the mechanism of ion channels.

Answer 6

1. ligand binds to subunit (usually channels are pentameres and binding occurs to alpha subunit)
2. binding causes conformational change that allows ions to flow through channel

Question 7

(3) Describe the mechanism of G protein-coupled receptors.

Answer 7

1. agonist changes conformation of serene and cytosine regulatory groups, which effects G protein binding
2. agonist binding causes GDP to be released from G protein in exchange for GTP
   3.

Question 8

(3) What are the two major second messenger systems modulated by G proteins?

Answer 8

cAMP and phopholipase C pathways

Question 9

(3) Describe the cAMP second messenger system.

Answer 9

1. G protein interacts with adenylase cyclase which creates a second messenger
2. G protein has inherent GTPase activity
3. Levels of cAMP are regulated by phophodiesterase
4. PKA are responsive to cAMP, phosphorylation of PKA leads to PKA action (phosphatase causes inactivation)

Question 10

(3) Describe the PIPC pathway.

Answer 10

1. G alpha q subunit activates PLC
2. PLC cleaves PIP2 into IP3 and DAG
   3a. IP3 binds to channel receptors that effect Ca+ concentration and calmodulin action
   3b. DAG activates PKC action and phosphorylation and activation of tyrosine kinases

Question 11

(3) Name the major G protein alpha subunits discussed in this course.

Answer 11

Gs (activates adenylyl cyclase), Gq (activates phopholipase C and Gi (inactivates adenylyl cyclase)

Question 12

(4) Name several general ways desensitization occurs due to receptor regulation

Answer 12

phosphorylation, endocytosis and proteolysis

Question 13

(4) Describe short-term mechanisms for receptor regulation.

Answer 13

1. phosphorylation of serene and threonine residues by the G-protein coupled receptor kinase (GRK)
2. GRK phosphorylation causes Gs protein inability to bind and receptor cannot be activated
3. removal of agonist, series and threonines are dephosphorylated by cellular phosphatases

Question 14

(4) Describe the mechanismlong-term receptor regulation

Answer 14

long-term desensitization occurs when receptors are trafficked to lysosomes and degraded

Question 15

(5) What is the meaning of Kd

Answer 15

1. describes the ratio of dissociation and association
2. describes the equilibrium dissociation constant
3. describes concentration of drug required to occupy 50% of drug sites

Kd can be used to describe the affinity of drug receptor binding with a lower Kd describing tight binding

Question 16

(6) Binding depends on complementarities between the drug and receptor determined by these forces:

Answer 16

ionic bonds (weak in biological aqueous systems)
covalent bonds
hydrogen bonds (directional)
van der Waals force
chemical structure (shape)
hydrophobic interactions (halogens are hydrophobic)
repulsive forces

Question 17

(6) Why are physiochemical and stereochemical forces important in drug binding?

Answer 17

drug’s ability to activate receptor depends on ability of drug and receptor to form a complex; the more interaction of contact residues with drug, the more complex stability