Receptor Theory 1 Flashcards
What is a drug?
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
Where do drugs act?
Whole organisms Isolated organs and tissues Specific Cell types Subcellular structures
What are some macromolecular targets for drug binding?
Enzymes Transporters Ion Channel Proteins Receptors - EC or IC Nucleic Acids
What is the general rule of lower potency drugs?
The lower the potency of the drug, the higher dose needed and more likely risk of side-effects
Give an example of binding site and ligand specificity
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
What are the criteria for hormone-receptor mediated events?
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
What are the models of receptor binding?
Lock and Key Zipper Model
What are the issues with the lock and key model?
some flexible drug molecules may adopt a different conformation which may be the wrong shape for binding
What is the strongest chemical bond between drugs and macromolecules?
Covalent bonding
What are the features of covalent bonding?
Strongest type of bond = -40-100kcal/mole Usually produces irreversible attachment Difficult to remove if toxicity occurs Not appropriate for agonism
What does the bond strength of ionic bonding depend upon?
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
What is the significance of ionisation in ionic bonding?
Ionised drugs are more water soluble where unionised forms are more lipid soluble which is important for absorption
How can you predict the degree of ionisation of ionisable groups?
Henderson-Hasselbach Equation pH = pKa + log10 [base form of drug]/[acid form of drug]
When is the degree of ionisation 50%?
pH = pKa
What are some significantly ionised groups at pH 7.4?
COOH NH2 SH POOH
What are the features of hydrogen bonding?
strength proportional to 1/d4 Usually 1-7kcal/mole
What are the major properties of receptors?
recognition saturability reversibility stereoselectivity agonist specificity
What is simple occupancy theory?
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
Prove that the ratio of association and dissociation rates are equal to the dissociation constant
Rate of association = k1D+R rate of dissociation = k2 DR K1D+R = k2DR K2/K1 = [D]+[R]/[DR] therefore Kd = [D]+[R]/[DR]
What is the equation for fractional occupancy?
[DR]/[Rt] = [D]/kd+[D]
What is the issue with the double reciprocal plot?
Associated with statistical errors
What is the Scratchard Plot Useful for?
What assumptions are made in single occupancy?
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
When is the Ec50 = Kd?
if the agonist is producing its responses in accordance with single occupancy theory
What is a partial agonist?
an agonist that can not produce the same maximal response as a full agonist even when occupying the full receptor population
How did Ariens modify simple occupancy theory to include the concept of partial agonists?
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
What are spare receptors?
When the drug can produce a maximal response without occupying all the receptors…these receptors are spare receptors
Why can a partial agonist never have spare receptors?
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
