Fall 2016

V. Pharmacological dose-response relationship

- The most common screening method to study receptor-ligand relationship is radio-ligand binding.

- Pharmacological Ligands include:

a. full agonist: activate a receptor maximally at a minimum concentration; has maximum efficacy
example: bromocriptin (dopamine agonist for D2 receptor) to treat Parkinson’s disease

b. partial agonist: activate a given receptor partially; has only partial efficacy
example: buprenorphine (opioid receptor for d, k and µ) to treat opioid addition or pain release

c. antagonist: inhibit receptor activation

example: haloperidol (dopamine antagonist) to treat bromocriptine poisoning and use as antidote
to cocaine

d. inverse agonist: inactivate a given receptor

example: classical example is GABA receptor where:
- benzodiazepines activates the receptor to cause sedation (anti-anxious), whereas
- R015-4513 activates the receptor to cause an apposite effect; anxiogenic and convulsions

e. allosteric agonist: does not bind to the receptor’s active site, but rather modulate effector site
example: barbiturates and ethanol induce sedation and anxiolytic (but still need g-aminobutyric
acid to activate GABA receptor).

- Ligand-Receptor interaction is determined by the following intrinsic properties:

a. affinity: integration of electrostatic forces, van der Waal forces, and the forces associated with
hydrogen bonds and hydrophobic bonds.
b. potency: drug concentration to produce 50% of the maximum effect.
c. efficacy: the ability of a ligand to elicit a response when binding to the receptor
d. specificity: the ability of a ligand to bind to a specific receptor
e. selectivity: the ability of a ligand to elicit a specific response when binding to the receptor
f. therapeutic index: the ratio of drug concentrations that produce an undesired effect to desire effect
(LD50/ED50).

Surya Nauli, Ph.D. 25

 Fall 2016

- Example for specificity of Ligand-Receptor interaction:

- GABAA is an ionotropic receptor, and benzodiazepine has specificity to activate GABAA, resulting in
sedative and anxiolytic (anti-anxiety) effects.
- GABAB is a G-protein coupled receptor, and baclofen has specificity to activate GABAB, resulting in
spasmolytic (relaxing) effect.

- Example for selectivity of Ligand-Receptor interaction:

- Benzodiazepin is known to activate GABAA receptor, which composes of 5 subunits.
- Benzodiazepin binding to subunit a1 or a5 will result in sedation.
- Benzodiazepin binding to subunit a2 or a3 (especially at higher dosage) will result in anxiolytic.

efficacy
100 100
% (+) effect

% (-) effect

LD50 = 2
50 50

ED50 = 1
potency

0 1 2 0 2 4
Log [concentration] Log [concentration]

full agonist with

allosteric agonist
100
full
agonist full agonist
with antagonist
50
% effect

partial
agonist
0
0 1 2 Dose
inverse
agonist

Surya Nauli, Ph.D. 26