L1+2 - Receptor Theory

Question 1

What is a drug?

Answer 1

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

Question 2

Drugs can act on:

Answer 2

Receptors
Enzymes 
Transporters
Ion Channels
Enzymes
Nucleic Acids

Question 3

Drug Specificity

Answer 3

If a drug has ready access within the organism to reach cellular macromolecules, the ability of the drug to bind and act selectively upon particular targets is highly dependent upon chemical structure and shape not only of the drug but also of the macromolecule

Question 4

Lock and Key model

Answer 4

Agonist considered to have 3D structure that fits ‘lock’, ie. the receptor.
Antagonists fit the lock but cannot open it
Flexible drugs may adapt different conformations, not all of which can correct for fitting into the lock. Eg. Insulin is very flexible peptide with a number of possible conformations

Question 5

Bonding Energies

Answer 5

Covalent = -40 to -110 kcal/mol
Reinforced Ionic = -10
Ionic = -5
Ion-diploe = -1 to -7
Dipole-dipole = -1 to -7
Hydrogen = -1 to -7
Charge Transfer (stacking) = -1 to -7
Hydrophobic Interactions = -1
Van der Waal's Interactions = -0.5 to -1

Question 6

Covalent Bonds

Answer 6

Formed by pairing of valence electrons, usually irreversible.
Some clinically useful drugs are covalent antagonists, but they can be difficult to remove if toxicity or adverse reactions onset

Question 7

Electrostatic Interactions

Answer 7

Between oppositely charged chemical groups, and bond strength is dependant on charge partaking in the interaction.

proportional to 1/d (d = distance between groups)

Question 8

Ionised Chemical Groups

Answer 8

Drugs existing as salts, ionised forms of drugs are more water soluble

Question 9

pKa =

And association with pH

Answer 9

pKa = -log(Ka)

If pKa = pH, 50% degree of ionisation, if pKa above 50%, more ionisation.

Question 10

Body pH and commonly ionised chemical moietys

Answer 10

pH = 7.35

COOH, NH2, SH, PO3H (phosphate)

Question 11

Hydrogen Bonding

Answer 11

Interaction between 2 electronegative atoms with a proton between them.
H atom covalently bonded to one atom, attracted to lone electron pair on other atom.
Strength proportional to 1/d^4

Question 12

Law of Mass Action

Answer 12

The principle that the rate of a chemical reaction is proportional to the concentrations of the reacting substances.

Question 13

Receptor Theory and Binding follows which laws?

Answer 13

Law of mass action

Laws of thermodyanmics

Question 14

Simple Occupancy Theory

Answer 14

D + R DR

E = (Emax . [D]) / (Kd + [D])
E = effect, Emax = max effect, Kd = dissociation constant

Does not take into account intrinsic activity (EFFICACY)
Proposed that an agonist has its maximum effect when bound to all receptor present.

Question 15

‘Zipper Model’

Answer 15

Suited to idea of flexible drugs, binding of drug occurs ‘bit by bit’ in a series

Question 16

Fractional Occupancy =

Answer 16

FO = [DR] / [Rt]

[Rt] = total receptors

Question 17

Estimating EC50

Answer 17

EC50 is the same numerically, as Kd - the concentration of drug which elicits a half-maximal response.

0.5(Emax)

Question 18

Partial Agonists

Answer 18

Can never cause as large a response as a full agonist

Question 19

Full Agonists

Answer 19

A weaker agonist will cause shift of curve to the right on a log concentration-response curve.

Question 20

Arien’s Modification to Simple Receptor Theory

Answer 20

Takes into account partial agonists
Response = FO x f
FO = fractional occupancy
f = intrinsic efficacy (0-1) 1 being a full agonist

Question 21

Nickerson’s Modification to Simple Receptor Theory

Answer 21

Spare receptors - not all receptors need to be liganded and activated in order to generate a maximal response

Question 22

Stephenson’s Modification to Simple Receptor Theory

Answer 22

Size of stimulus is dependant on agonist fraction occupancy, and efficacy

Question 23

Super Agonist

Answer 23

Efficacy > 100%

Question 24

Full Agonist

Answer 24

Efficacy = 100%

Question 25

Partial Agonist

Answer 25

Efficacy = 0% < E > 100%

Question 26

Silent Agonist

Answer 26

E = 0%

Question 27

Inverse Agonist

Answer 27

E < 0%

Question 28

Stimulus (S) =

Answer 28

S = E([D]/Kd)
or
S = E . FO

Question 29

Reversible Competitive Antagonists

Answer 29

Binds to same site and agonists to prevent block, has 0 efficacy
Shift log concentration-response curve to the right
Emax stays the same, Kd decreases

Question 30

Schild Plot

Answer 30

Dose ratios calculated by Kd of drug with antagonist / Kd of drug without antagonist
Can then be plotted on a schild plot to allow for extrapolation of Kd of antagonist
Plot log of antagonist concentration on x-axis, and (dose ratio minus 1 on y-axis)

Question 31

pA2 =

Answer 31

pA2 = -log(A2)

Question 32

Reversible Non-Competitive Antagonism

Answer 32

Binds allosterically to prevent activity of agonist, or prevent binding of it all together

Eg Ketamine and NMDAR

Emax decreases, Kd stays the same

Question 33

Irreversible Competitive Antagonism

Answer 33

Naloxazone MOP1 receptor antagonists
Binds covalently to active site
Kd stays same, Emax reduced - cannot be reversed by increasing agonist conc.

Question 34

Inverse Agonists

Answer 34

Increase preference to non-active receptor form

Eg B2ARs can produce a basal cAMP level due to spontaneous activation, occurs in cells with high levels of expression - inverse agonist increases preference of receptor to remain in non-active state

Question 35

Cooperativity

Answer 35

Phenomenon in enzymes and receptors, altered affinity (can be positive or negative) for binding of other ligands
Homotropic = ligand influences cooperativity of same ligand
Heterotropic = of other ligand

Question 36

Hill Plot

Answer 36

Gradient of a line (Hill coefficient) shows cooperativity
n > 1 = positive cooperatvity
n = 0 = no cooperativity
n < 1 = negative cooperativity

Question 37

Allosteric Modulators

Answer 37

Can be PAM or NAM
modulates activity of GPCR
Useful as potentiates the effect of endogenous ligand at endogenous concentration, therefore usually has reduced chance of side effects