DavidsonX – D001x – Medicinal Chemistry Chapter 5 – Receptors Part 2 – Ligands Video Clip – Ligand Types
Ligands can have different effects on a receptor. Each type of ligand can be readily classified according to its behavior. A type of ligand is the full agonist. The term agonist refers to a compound that binds a receptor and elicits a response (E). Full agonists elicit the same level of full response (E = Emax = 100%) as the endogenous ligand of the receptor. Graphically, a receptor-ligand interaction is plotted as response (E/Emax) vs. log [L]. The relationship is sigmoidal. A full agonist approaches full response (E/Emax = 1.0) as log [L] reaches relatively high levels.
response vs. log [L] - full agonist
1 0.9 0.8 0.7 x
a 0.6 m
E 0.5
/
E 0.4 0.3 0.2 0.1 0 log [L]
Two ligands can achieve a full response without being equivalent. Ligands can differ with respect to the concentration required to trigger a response. A ligand that affects a response at a lower concentration has a higher potency. Potencies are measured as the effective ligand concentration required to reach a 50% response – EC50 or, in these graphs, log [EC50]. A more potent ligand has a lower EC50 value. full agonist comparison
1 0.9 full agonist 1 0.8 (more potent) full agonist 2 0.7 (less potent) x a 0.6 log EC
m 50
E 0.5
/
E 0.4 0.3 log EC 0.2 50 0.1 0 log [L]
Partial agonists also cause a response, but they cannot reach the same, 100% response level of the endogenous ligand. Partial agonists also show a sigmoidal relationship between response and log [L]. The potency of a partial agonist is still reported as an EC50 value, but it does not occur at 50% response. The EC50 value instead occurs at 50% of the maximum response possible for that partial agonist. For example, if a partial agonist can only achieve a maximum response of 60%, then it's log EC50 would be measured at just 30% response. Partial agonists and full agonists typically bind at the same site. This similarity in binding gives rise to an interesting effect. If a full agonist is at levels sufficient to cause a full reponse and a partial agonist is added, then the response will decreases. If partial agonist levels are further elevated, the response will eventually decrease to the maximum response of the partial agonist. The partial agonist can displace the full agonist from the binding site and decrease the response.
response vs. log [L] - partial agonist (Emax = 60%)
1 0.9 full agonist with added 0.8 partial agonist 0.7 x
a 0.6
m partial agonist alone
E 0.5
/
E 0.4 0.3 log EC 0.2 50 (50% of max response) 0.1 0
log [L]
Antagonists bind a receptor, do not cause a response, and block the response caused by an agonist. Based on this description an antagonist by itself has no effect the response of a receptor. An antagonist does, however, decrease an agonist's response. effect of an antagonist on a full agonist
1 0.9 0.8 0.7 x
a 0.6 m
E 0.5
/
E 0.4 0.3 0.2 0.1 0
log [antagonist]
Inverse agonists are very interesting ligands because they decrease the response of a receptor. Many receptors can cause a response without being bound to a ligand. Such receptors are said to have constituent activity. The level of constituent activity is typically very low and may only be a few percent of Emax. When an inverse agonist is added to a constituently active receptor, the response of the receptor approaches zero.
effect of an inverse agonist on a constituently active receptor
1 0.9 0.8 0.7 x
a 0.6 m
E 0.5
/
E 0.4 0.3 0.2 0.1 0
log [inverse agonist]