Receptor Theory 1

Question 1

What is a drug?

Answer 1

A chemical substance that is able to interact more or less selectively with constiuents of living organisms, in order to bring about changes in the physiological function of the organism

Question 2

Where do drugs act?

Answer 2

Whole organisms Isolated organs and tissues Specific Cell types Subcellular structures

Question 3

What are some macromolecular targets for drug binding?

Answer 3

Enzymes Transporters Ion Channel Proteins Receptors - EC or IC Nucleic Acids

Question 4

What is the general rule of lower potency drugs?

Answer 4

The lower the potency of the drug, the higher dose needed and more likely risk of side-effects

Question 5

Give an example of binding site and ligand specificity

Answer 5

Angiotensin acts strongly on vascular smooth muscle and kidney tubule but has little effect on other types of smooth muscle. A small chemical change in angiotensin can inactivate angiotensin as it fails to bind the receptor

Question 6

What are the criteria for hormone-receptor mediated events?

Answer 6

Receptors must possess structural and steric specificity for the hormone and closely related drugs Receptors are saturable and limited Hormone-receptor binding is cell-specific Receptors must possess high affinity for the ligand at physiological concentrations Once the ligand binds the receptor, a recognisable chemical event must occur

Question 7

What are the models of receptor binding?

Answer 7

Lock and Key Zipper Model

Question 8

What are the issues with the lock and key model?

Answer 8

some flexible drug molecules may adopt a different conformation which may be the wrong shape for binding

Question 9

What is the strongest chemical bond between drugs and macromolecules?

Answer 9

Covalent bonding

Question 10

What are the features of covalent bonding?

Answer 10

Strongest type of bond = -40-100kcal/mole Usually produces irreversible attachment Difficult to remove if toxicity occurs Not appropriate for agonism

Question 11

What does the bond strength of ionic bonding depend upon?

Answer 11

Amount of charge on each group Proportional to 1/d2 where d= distance between charges Usually around -5kcal/mole in polar environments Can be stronger if ions close to more hydrophobic environments

Question 12

What is the significance of ionisation in ionic bonding?

Answer 12

Ionised drugs are more water soluble where unionised forms are more lipid soluble which is important for absorption

Question 13

How can you predict the degree of ionisation of ionisable groups?

Answer 13

Henderson-Hasselbach Equation pH = pKa + log10 [base form of drug]/[acid form of drug]

Question 14

When is the degree of ionisation 50%?

Answer 14

pH = pKa

Question 15

What are some significantly ionised groups at pH 7.4?

Answer 15

COOH NH2 SH POOH

Question 16

What are the features of hydrogen bonding?

Answer 16

strength proportional to 1/d4 Usually 1-7kcal/mole

Question 17

What are the major properties of receptors?

Answer 17

recognition saturability reversibility stereoselectivity agonist specificity

Question 18

What is simple occupancy theory?

Answer 18

binding of a drug to an appropriate receptor or binding site is reversible and its extent is determined by the following reversible equilibrium D+R DR

Question 19

Prove that the ratio of association and dissociation rates are equal to the dissociation constant

Answer 19

Rate of association = k1D+R rate of dissociation = k2 DR K1D+R = k2DR K2/K1 = [D]+[R]/[DR] therefore Kd = [D]+[R]/[DR]

Question 20

What is the equation for fractional occupancy?

Answer 20

[DR]/[Rt] = [D]/kd+[D]

Question 21

What is the issue with the double reciprocal plot?

Answer 21

Associated with statistical errors

Question 22

What is the Scratchard Plot Useful for?

Question 23

What assumptions are made in single occupancy?

Answer 23

drug effect is produced by 1 molecule to 1 receptor

drug effect is proportional to the fraction of receptor occupied

drug effect is measured when binding to the receptor population has reached equilibirum

Free drug concetration is in equilibrium with receptors producing the effect and is assumed to be the same as the concetration initially added

Question 24

When is the Ec50 = Kd?

Answer 24

if the agonist is producing its responses in accordance with single occupancy theory

Question 25

What is a partial agonist?

Answer 25

an agonist that can not produce the same maximal response as a full agonist even when occupying the full receptor population

Question 26

How did Ariens modify simple occupancy theory to include the concept of partial agonists?

Answer 26

Proposed that agonists have different intrinsic acitivities (efficacy)(f) and thus this could be measured on a scale of 0-1 - 1 = full agonist where 0 = antagonist

Response = fractional occupancy x f

Question 27

What are spare receptors?

Answer 27

When the drug can produce a maximal response without occupying all the receptors…these receptors are spare receptors

Question 28

Why can a partial agonist never have spare receptors?

Answer 28

Because even when occupying all the receptors it cannot elicit a maximal response, and removal of any portion of the receptors will reduce the response