Endocrinology 13th October 2016 Receptor Pharmacology Pharmacology is the study of drug action; molecular pharmacology aims to describe this in terms of biochemistry. The discipline underpins attempts to discover new drugs and therapeutic strategies as well as addressing fundamental question in biology of how cells communicate with each other. Receptors Corpora non agunt nisa fixate - substances do not work unless bound: stated by Paul Erlich, 1913. Naturally occurring receptors are molecules that bind signalling molecules (neurotransmitters, hormones, autocoids) and consequently activate cells. Natural Receptors G-protein-linked receptors (GPCRs) e.g. muscarinic acetylcholine, adrenergic, histaminergic. Ion channels e.g. nicotinic receptors Gene transcription e.g. steroid receptors Enzymes e.g. tyrosine kinases, guanylate cyclases, cytokines What can drugs do? Agonists - activate receptors Antagonists - block receptors Depending on the conditions, some drugs show mixed behaviour, acting as agonists in some situations and antagonists in others. Antagonists Binds to receptor and stops the natural ligand (hormone, neurotransmitter, etc .... from binding). Competitive or non-competitive (with natural hormone) Reversible (can be "washed off") or irreversible. Can be physiological (stopping something directly) or chemical (modify ligand instead of acting on the receptor e.g. antibodies). Many receptors show slight basal activity (happens when nothing is bound) even if no ligand is bound. If the antagonist can stop this as well, it is known as an inverse agonist.
Endocrinology 13th October 2016 Key Concept 1 - Affinity Affinity is the tendency (or strength) of a ligand to bind to the receptor. - How well the hormone binds to its receptor. The process is governed by various properties: Structure/shape: complementarily (lock and key concept and induced fit concept) Intermolecular forces: ionic interactions, hydrogen bonds, van der Walls (short range interaction) The greater the intermolecular force between the ligand and the receptor, the high the affinity. Typically in biological systems, the ligand and receptor bind reversibly, however, sometimes the intermolecular forces are so great the binding is irreversible. Law of Mass Action The principle of the Law of Mass Action: the rate of a chemical reaction is directly proportional to the molecular concentration of the reacting substances. The more hormones the faster it binds. In reality: Just a very simple mathematical model to explain the behaviour of solutions in dynamic equilibrium. Law of Mass Action applied to receptor binding Equilibrium is reached when the rate at which new LR complexes are made equals the rate at which LR complexes dissociate. - the rate at which the hormone binds must equal the rate at which the complex dissociates; forms stability. [R] + [4] [ER] R = Receptor L = Ligand LR = Ligand receptor complex Kon = Association rate constant (on-rate) Koff = Dissociation rate constant (off-rate) At equilibrium the equation is: [L]* [R] x kpn = [LR] x *_** This can be rearranged [L] Ć [R] [LR] K Kd = Equilibrium dissociation constant
Endocrinology 13th October 2016 At equilibrium, when [L] equals Kd, this means half the receptors are free and half the receptors are in complex. Equilibrium is in favour