Receptors & Drug action at Receptors Chapter 4 Lecture 8 Dr Brajesh Kumar

Introduction Target for drugs 1. Enzymes (major) 2. Receptors Drugs which interact with receptors are amongst the most important in medicine and provide treatment for ailments such as pain, depression, Parkinson's disease,psychosis, heart failure, asthma, and many other problems.

What is a Receptor? The term “receptor” specifically refers to proteins that participate in intracellular communication via chemical signals A receptor is a protein molecule embedded within the cell membrane with part of its structure facing the outside of the cell. The beneficial therapeutic effects and unwanted toxic effects of drugs are elicited through interactions with proteins -Enzymes (aspirin + cyclooxygenase) -Transporters/Carriers (Prozac + serotonin reuptake transporter) -Ion Channels (local anesthetics + Na+ channels) -Receptor Proteins (cimetidine + histamine receptor) ---Upon recognition of an appropriate chemical signaling molecule (ligand), receptor proteins transmit the signal into a biochemical change in the target cell ----- Ligands include drugs as well as endogenous signaling molecules such as hormones and neurotransmitters

The receptor role Communication is essential for all the control in the body's organs and functions. Control and communication come primarily from the brain and spinal column (the central nervous system—CNS) which receives and sends messages via a vast network of nerves Message as being an electrical 'pulse' which travels down the nerve cell towards the target, The nerves do not connect directly to their target cells. They stop just short of the cell surface 100 Aº, Chemical messenger can diffuse across the gap between the nerve ending and the cell . It can bind and interact with a receptor & result in a biological response/action.

The Lock and Key Model of Ligand- Receptor Interaction -A ligand such as a hormone or neurotransmitter (the "key") bind to specific receptors (the "lock”) -this binding "unlocks" the cell's response. -many drugs work by mimicking a naturally occurring hormone or neurotransmitter -if the drug causes the receptor to respond in the same way as the naturally occurring substance, then the drug is referred to as an agonist -these are drugs that can “pick the lock”. -other drugs work in the opposite way - as antagonists -these drugs bind to the receptor, but do not produce a response. -because the drug prevents the receptor from binding to the normal hormone or neurotransmitter, it has an inhibitory effect on the naturally occurring substance.

Chemistry of Drug-Receptor Interactions Most drug-receptor interactions -reversible -weak chemical bonds Irreversible drug-receptor interactions -not common -strong chemical bonds (covalent) -e.g. aspirin, anti-tumour drugs -usually undesirable -reversal of effects/toxicity -mutagenicity/carcinogenicity Hormones and neurotransmitters can be distinguished by the route they travel and by the way they are released, but their action when they reach the target cell is the same. They both interact with a receptor and a message is received. The cell responds to that message, adjusts its internal chemistry accordingly and a biological response results.

Neurotransmitters It include compounds(messenger) such as Acetylcholine, noradrenaline, dopamine,7-aminobutanoic acid (GABA), serotonin, 5-hydroxytryptophan, and even glycine A nerve releases only one type of neurotransmitter & receptor awaits it on the target cell will be specific for that messenger

Difference between enzymes & receptors ? In receptor there will be an area which has the correct shape to accept the incoming messenger. This area is known as the binding site and is analogous to the active site of an enzyme -Chemical messenger does not undergo a chemical reaction It fits into the binding site of the receptor protein, passes on its message and then leaves unchanged.

How does the message get received? If no reaction takes place, what has happened? How does the chemical messenger tell the receptor its message and how is this message conveyed to the cell? Message get received or conveyed is related with shape The messenger binds to the receptor and induces it to change shape. This change subsequently affects other components of the cell membrane and leads to a biological effect. There are two main components involved: Ion channels (2) Membrane-bound enzymes

Ion channels & Membrane-bound enzymes Messenger Receptor Cell membrane Enzyme Active Sites Ion channels Cell Cytoplasm Membrane-bound enzymes

The design of agonists Following requirements in turn The drug must have the correct binding groups. The drug must have these binding groups correctly positioned. The drug must be the right size for the binding site. Agonist (e.g. drug, hormone, neurotransmitter) binding induces a conformational change in the receptor from the inactive to active state Conformational change to active state can also occur spontaneously in the absence of agonist (random kinetic fluctuations) Agonist dramatically increases the probability of conformational change and stabilizes the active state

The design of antagonists Antagonists acting at the binding site Antagonists acting outwith the binding site- Allosteric antagonists & Antagonism by the 'umbrella’ effect • Bind to receptors, but do not activate signal transduction mechanisms • Biological effects derive from preventing agonist (drugs, endogenous) binding and receptor activation Competitive Antagonists -bind to same site on receptor as agonists -inhibition can be overcome by increasing agonist concentration (reversible) -primarily affect agonist potency -clinically useful Non-Competitive Antagonists -bind covalently to same site as agonist (irreversible) or to a site distinct from that of agonist (irreversible or reversible) -inhibition cannot be overcome by increasing agonist concentration -primarily affect efficacy -limited clinical use

The switch: Allosteric inhibition Allosteric means “other site” Active site E Allosteric site These enzymes have two receptor sites One site fits the substrate like other enzymes The other site fits an Antagonist or inhibitor molecule Antagonists fits into allosteric site

The allosteric site the enzyme “on-off” switch Active site E Allosteric site empty E Conformational change Substrate fits into the active site Antagonist molecule is present Substrate cannot fit into the active site The Antagonist molecule is absent Antagonist fits into allosteric site Antagonist behaves just like Inhibitors

Desensitization • Effect of a drug often diminishes when given continuously or repeatedly • desensitization, tachyphylaxis, refractoriness, resistance, tolerance • receptor-mediated and non-receptor-mediated mechanisms Receptor Mediated - loss of receptor function - reduction of receptor number Non-Receptor Mediated - reduction of receptor-coupled signaling components - reduction of drug concentration - physiological adaptation