Agonists and Antagonists

1. Agonists and Antagonists Tim Bloom, Ph.D. 206 Maddox Hall 893-1712

2. Overview • Introduction to ligand action • Introduction to agonists • Introduction to antagonists

3. Ligand Binding • Ligands and receptors are in a dynamic relationship R + L RL • Amount of RL depends on • Concentration of L and R • Affinity of R for L

4. Ligands bind with several features Saturability Reversibility (usually) Dose response (response may be seen at level of cell or organism, rather than level of receptor) Ligand Binding % bound receptors dose

5. All ligand molecules for a receptor can bind all available receptors Percentage of binding depends on: Concentration of each Affinity for each other Ligand Binding R L R L

6. Kd = concentration of ligand resulting in 50% of receptors being bound Measure of affinity of ligand for receptor Inverse relationship to affinity Ligand Binding % bound receptors Kd dose

7. Classifying Ligands • All ligands bind their receptor(s) • Ligands are classified by effect upon binding to receptor • Agonist if receptor changes behavior • Ion channel opens • Receptor kinase is activated • Etc. • Antagonist if receptor does nothing

8. Agonists and Effects • Agonists produce effects upon binding • Amount of effect related to amount of binding • Increased binding = increased effect • Decrease binding = decrease effect • All receptors bound = no more increase possible

9. Dose Response • Effect of binding varies with dose • Small dose, small effect • Larger dose, larger effect

10. Dose response • 100% receptor binding does not guarantee 100% effect • Full agonist • Partial agonist A B

11. Efficacy • Ability to produce an effect upon binding receptor • All agonists have some efficacy • Efficacy ranges from 0-1 • Full agonist has efficacy = 1 • Partial agonists have 0 < efficacy < 1 • Accurate name is pharmacological efficacy

12. Efficacy • Based on two receptor conformations • Inactive vs. active R R* • Agonists push receptor to active form • Amount of push reflects efficacy • Full agonists push strongly • Partial agonists push weakly

13. Antagonist Ligands • Antagonists: pharmacological efficacy = zero • Produce no effect on receptor • Don’t change activity state of receptor • Antagonists DO have clinical efficacy • Can produce therapeutic effect • Prevent action of endogenous agonist • Curare is an antagonist of a sodium channel

14. Antagonists • Classified by how and where they bind • Binding strength • Reversible • Non-reversible (truly or effectively) • Binding site • Competitive • Non-competitive

15. Competitive Antagonists • Binds same site as agonist • If reversible binding, excess agonist overcomes • If irreversible binding, cannot be overcome R L L

16. Non-competitive Antagonists • Bind receptor somewhere else • Cannot be competed away by agonist • Effect cannot be overcome by agonist L R L

17. Review • Ligands bind to receptors • Form chemical bonds • Interaction depends on 3D shape of each • Classify ligand by receptor response • Agonist if receptor changes • Antagonist in no receptor change

18. Review • Agonists have pharmacological efficacy • Full agonist • Partial agonist • Antagonists lack pharmacological efficacy • Can show clinical efficacy • How they bind affects their usefulness