L1+2 - Receptor Theory Flashcards
What is a drug?
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
Drugs can act on:
Receptors Enzymes Transporters Ion Channels Enzymes Nucleic Acids
Drug Specificity
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
Lock and Key model
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
Bonding Energies
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
Covalent Bonds
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
Electrostatic Interactions
Between oppositely charged chemical groups, and bond strength is dependant on charge partaking in the interaction.
proportional to 1/d (d = distance between groups)
Ionised Chemical Groups
Drugs existing as salts, ionised forms of drugs are more water soluble
pKa =
And association with pH
pKa = -log(Ka)
If pKa = pH, 50% degree of ionisation, if pKa above 50%, more ionisation.
Body pH and commonly ionised chemical moietys
pH = 7.35
COOH, NH2, SH, PO3H (phosphate)
Hydrogen Bonding
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
Law of Mass Action
The principle that the rate of a chemical reaction is proportional to the concentrations of the reacting substances.
Receptor Theory and Binding follows which laws?
Law of mass action
Laws of thermodyanmics
Simple Occupancy Theory
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.
‘Zipper Model’
Suited to idea of flexible drugs, binding of drug occurs ‘bit by bit’ in a series
Fractional Occupancy =
FO = [DR] / [Rt]
[Rt] = total receptors
Estimating EC50
EC50 is the same numerically, as Kd - the concentration of drug which elicits a half-maximal response.
0.5(Emax)
Partial Agonists
Can never cause as large a response as a full agonist
Full Agonists
A weaker agonist will cause shift of curve to the right on a log concentration-response curve.
Arien’s Modification to Simple Receptor Theory
Takes into account partial agonists
Response = FO x f
FO = fractional occupancy
f = intrinsic efficacy (0-1) 1 being a full agonist
Nickerson’s Modification to Simple Receptor Theory
Spare receptors - not all receptors need to be liganded and activated in order to generate a maximal response
Stephenson’s Modification to Simple Receptor Theory
Size of stimulus is dependant on agonist fraction occupancy, and efficacy
Super Agonist
Efficacy > 100%
Full Agonist
Efficacy = 100%
Partial Agonist
Efficacy = 0% < E > 100%
Silent Agonist
E = 0%
Inverse Agonist
E < 0%
Stimulus (S) =
S = E([D]/Kd)
or
S = E . FO
Reversible Competitive Antagonists
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
Schild Plot
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)
pA2 =
pA2 = -log(A2)
Reversible Non-Competitive Antagonism
Binds allosterically to prevent activity of agonist, or prevent binding of it all together
Eg Ketamine and NMDAR
Emax decreases, Kd stays the same
Irreversible Competitive Antagonism
Naloxazone MOP1 receptor antagonists
Binds covalently to active site
Kd stays same, Emax reduced - cannot be reversed by increasing agonist conc.
Inverse Agonists
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
Cooperativity
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
Hill Plot
Gradient of a line (Hill coefficient) shows cooperativity
n > 1 = positive cooperatvity
n = 0 = no cooperativity
n < 1 = negative cooperativity
Allosteric Modulators
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
