Drug Chemistry and Toxicology CHE 618 Alexander Nazarenko

The Receptor Concept The Nature of Drug Receptors Drug Parameters: Affinity and Efficacy The Langmuir Isotherm equation

Opioid receptor Insulin receptor Transmembrane receptor

Occupation theory Drug effect is directly proportional to number of receptors occupied Drug effect ceases as drug-receptor complex dissociate Ariens & Stephenson theory introduced terms of "affinity" & "efficacy" Affinity: ability of the drug to combine with receptor to create drug-receptor complex Efficacy: ability of the drug-receptor complex to initiate a response Affinity “drug-receptor interaction” is governed by the law of mass action. In this theory Agonist: drug with high affinity & high intrinsic activity Partial agonist: drug with high affinity & low intrinsic activity Antagonist: drug with high affinity & low intrinsic activity Rate theory The activation of receptors is directly proportional to the total number of encounters of the drug with its receptors per unit time Pharmacological activity is directly proportional to the rate of dissociation & association not number of receptors occupied Agonist: drug with fast association & fast dissociation Partial agonist: drug with intermediate association & intermediate dissociation Antagonist: drug with fast association & slow dissociation Induced fit theory As the drug approaches the receptor the receptors alters the conformation of its binding site to produce drug—receptor complex

From the Greek αγωνιστής (agōnistēs), contestant; champion; rival < αγων (agōn), contest, combat; exertion, struggle < αγω (agō), I lead, lead towards, conduct; drive An agonist is a chemical that binds to a receptor and triggers a response. Whereas an agonist causes an action, an antagonist blocks the action of the agonist and an inverse agonist causes an action opposite to that of the agonist.

Drug + Receptor[Drug/Receptor Complex] Action K

β = 100K = 1/100 = 0.01 The Langmuir Isotherm

1/a 1/C a C C/a C Various plots Lineweaver–Burk plot Hanes–Woolf plot

Lineweaver–Burk or double-reciprocal plot of kinetic data, showing the significance of the axis intercepts and gradient. Michaelis-Menten Plot relating the reaction rate V to the substrate concentration [S]. Michaelis–Menten kinetics

Agonists Partial Agonist Antagonist Antagonists bind to receptors but do not activate them. This results in receptor blockage, inhibiting the binding of other agonists. Inverse Agonist Partial agonists do not activate receptors thoroughly, causing responses which are partial compared to those of full agonists Full agonists are able to activate the receptor and result in a maximal biological response. Inverse agonists reduce the activity of receptors by inhibiting their constitutive activity.

+1 0 Functional Response Log[Drug] Full Agonist Partial Agonist Neutral Antagonist Full Inverse Agonist

Competitive Antagonism A1 + Receptor{A1 Receptor} effect A2 + Receptor {A2 Receptor}

R A1 A2 R A1 R A2 R A1 A2 Receptor-A1 is active Receptor-A1-A2 is active

Similar: In coordination chemistry Metal Ion + Ligand 1 + Ligand 2 In enzyme kinetics Enzyme + Substrate + Inhibitor

Dose-response curve What is there that is not poison? All things are poison and nothing without poison Solely the dose determines that a thing is not a poison