Endocrinology 15 - Pharmacology Pharmacology - Study of drug action on receptors - Molecular pharmacology - how the biochemistry of what's going on underpins the signalling and response - Attempts to discover new drugs and therapeutic targets/strategies - Addresses fundamental research question regarding cellular communication Ligands can be divided into 3 classes; - Agonists - activate receptors o May be partial or full o Full agonist - turns on receptors at the maximum amount " If you put on more agonist the biological response won't go up anymore . Truthfully, we won't know until something better comes along - Antagonists - block receptors o Stops the natural ligand binding o Competitive " Can't catch any more ligands o Non-competitive o Reversible " Can't get rid of the antagonist o Irreversible " Covalently binds to the receptor and can no longer remove the antagonist - Inverse agonists - deactivate receptors Some ligands may show mixed behaviours depending on the situation 100 - Full agonist Partial agonist Biological response (%) Terms -Most likely will come 50 Basal activity 0- Drug concentration Weak partial agonist Neutral antagonist Inverse agonist T?BS - Partial agonist: The ligand can be happier with another receptor but are okay with this one - 20% of our receptors are spontaneously on - constitutive activity o On even in the absence of a ligand o Inverse agonist - stops it from turning on at all Terms: - Affinity:
o The tendency (or strength) of a ligand to bind to its receptor . How tightly it binds, how many bonds etc. " High affinity ones make better drugs - Fractional occupancy o The fraction of receptors occupied at a particular ligand conc. (at any one time) - Efficacy o The degree to which different agonists produce a response even when occupying the same proportion of receptors - Potency o Amount of drug needed to produce a defined effect Affinity Governed by various properties - Structure/shape complementarity o Shape of receptor has to match the shape of the binding site of the receptor - Intramolecular forces between ligand and receptor E.g. lonic / hydrogen bonding / Van der Waals forces o Higher intermolecular force = high affinity These interactions are reversible Measuring affinity - An equilibrium exists between free and occupied receptors o This is reached when the rate of formation of new LR complexes equals the dissociation rate of LR complexes - This relates to two receptors; o K(on) - how quickly it binds o K(off) - how quickly it dissociates [R] + [L] [LR] - At equilibrium: o The ligands and receptors at the K(on) rate o Is equal to the ligand-receptor complex at the K(off) rate [R] x [L] x kon = [LR] x Koff - The we can rearrange it [LR] [L] x [R] = Koff Kon - We term this Kd (dissociation constant) o Comparing how fast they are coming on compared to how fast they come off
Koff SÃO = Ka on Fractional Occupancy - Kd