Full agonists The “agonists” referred to so far are FULL AGONISTS Able to produce a maximum response for the tissue Even though only a fraction of the receptors are occupied

Curve for a full agonist 100 75 % Maximum response Typical curve for a full agonist 50 25 0.001 0.01 0.1 1 10 100 log conc (µM)

Curves for Full agonist and Partial agonist 100 75 % Maximum response PARTIAL 50 25 0.001 0.01 0.1 1 10 100 log conc (µM)

Relationship between occupancy and response FULL 100 80 60 PARTIAL Response (% maximum) 40 20 ANTAGONIST 0.0 0.2 0.4 0.6 0.8 1.0 Fractional occupancy

Differences between Full and Partial agonists FULL agonist - produces maximum response even when only a FRACTION of receptors are occupied PARTIAL agonist - CANNOT produce a maximum tissue response even when ALL receptors are occupied Note the curves are not parallel

Why is there a difference? The reason is due to EFFICACY Full agonists are said to have a higher efficacy than partial agonists What is efficacy? The ability of the drug-receptor complex to produce a response In other words how well a drug produces an effect - IN A PARTICULAR SYSTEM i.e. can vary tissue to tissue - even when the RECEPTORS are the SAME

Mathematical explanation Response depends upon characteristics of the TISSUE characteristics of the DRUG Response = ƒ Ntot XA XA + Kd ƒ (transducer function) Ntot (number of receptors) Kd (dissociation constant)  (intrinsic efficacy) ( ) } Properties of the TISSUE } Properties of the DRUG

Inverse agonists Do not confuse with an antagonist!!! Receptors can exist in 2 conformational states –”2 state model” These are “resting” and “activated” Agonists, antagonists and inverse agonists have differing binding affinities to these states

Two-state model R R* Inverse agonist Agonist resting activated RESP resting activated Antagonist

Recommended Reading Agonists Medical Pharmacology at a Glance, 5th Ed: Page 11 Pharmacology, 5th Ed: Pages 11-14 Basic and Clinical Pharmacology Online Book: Section I, Chapter 2, Relation between drug concentration and response, Partial Agonists