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Receptor ppt
- 1. By Prof. Rakesh D.Amrutkar Head of Department, Pharmaceutical Chemistry Mahatma Gandhi Vidyamandir’s Samajshri Prashantdada Hiray College of Pharmacy, Malegaon. Drug Receptor 1
- 2. 2 First postulatedby John Langley (1878) ◦ Established after his experiments using nicotine and curare analogues on muscle contraction. Furthered by Paul Ehrlich (1845-1945) ◦ Demonstrated that stereoselectivity was essential in drug-receptor signaling.
- 3. PAUL EHRLICH 1845-1945 Drugscannot act unless they are bound to receptors 3
- 4. RECEPTOR: A receptor isthe specific chemical constituent of the cell with which a drug interacts to produce it’s pharmacological effects. Some receptor sites have been identified with specific parts of proteins and nucleic acids. In most cases, the chemical nature of the receptor site remains doubtful. Any cellular macromolecule that a drug binds to initiate its effects. 4
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- 6. Chemical Messengers Neurotransmitters: Chemicalsreleased from nerve endings which travel across a nerve synapse to bind with receptors on target cells, such as muscle cells or another nerve. Usually short lived and responsible for messages between individual cells. Hormones: Chemicals released from cells or glands and which travel some distance to bind with receptors on target cells throughout the body. • Chemical messengers ‘switch on’ receptors without undergoing a reaction 6
- 7. Drug: A chemicalsubstance that interacts with a biological system to produce a physiologic effect. All drugs are chemicals but not all chemicals are drugs. The ability to bind to a receptor is mediated by the chemical structure of the drug that allows it to interact with complementary surfaces on the receptor. Once bound to the receptor an agonist activates or enhances cellular activity. 7
- 8. Binding site ◦specific point of ligand & receptor Affinity ◦ attraction ◦ physical & electrical fit NT or drug binds to receptor ◦ or activity of neuron ◦ excite or inhibit Drugs mimic or block NT message 8
- 9. Receptor changesshape Excitation or Inhibition.. ◦ Determined by nature of receptor ◦ receptor subtypes NOT NT NT binds to receptor NT = key Receptor = lock 9
- 10. Receptor A NT Ligand bindsto receptor 10
- 11. Receptor BReceptor A SameNT can bind to different Receptor But different part of NT NT 11
- 12. Receptor BReceptor A SameNT can bind to different Receptor But different part of NT NT 12
- 13. Receptor BReceptor A NT Specificityof Drugs Drug A Drug B 13
- 14. NT fitsreceptor site key & lock Change structure of drug... ◦ change its affinity increase or decrease ◦ may bind to different receptor 14
- 15. Structure and functionof receptors • Globular proteins acting as a cell’s ‘letter boxes’ • Located mostly in the cell membrane • Receive messages from chemical messengers coming from other cells • Transmit a message into the cell leading to a cellular effect • Different receptors specific for different chemical messengers • Each cell has a range of receptors in the cell membrane making it responsive to different chemical messengers 15
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- 18. Mechanism • Receptors containa binding site (hollow or cleft in the receptor surface) that is recognised by the chemical messenger • Binding of the messenger involves intermolecular bonds • Binding results in an induced fit of the receptor protein • Change in receptor shape results in a ‘domino’ effect • Domino effect is known as Signal Transduction, leading to a chemical signal being received inside the cell • Chemical messenger does not enter the cell. It departs the receptor unchanged and is not permanently bound 18
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- 20. ENZYME Binding site ofReceptor • A hydrophobic hollow or cleft on the receptor surface - equivalent to the active site of an enzyme • Accepts and binds a chemical messenger • Contains amino acids which bind the messenger • No reaction or catalysis takes place Binding site Binding site 20
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- 22. Messenger Binding • Bindingsite is nearly the correct shape for the messenger • Binding alters the shape of the receptor (induced fit) • Altered receptor shape leads to further effects - signal transduction Messenger Induced fit M 22
- 23. • Ionic • H-bonding •van der Waals Bonding forces Example: Receptor Binding site vdw interaction ionic bond H-bond Phe Ser O H Asp CO2 Messenger Binding 23
- 24. Substrate Binding • Inducedfit - Binding site alters shape to maximize intermolecular bonding Bonding forces Intermolecular bonds not optimum length for maximum binding strength Intermolecular bond lengths optimised Phe Ser O H Asp CO2 Induced Fit Phe Ser O H Asp CO2 24
- 25. Overall process ofreceptor/messenger interaction M M ER • Binding interactions must be: - strong enough to hold the messenger sufficiently long for signal transduction to take place - weak enough to allow the messenger to depart • Implies a fine balance • Drug design - designing molecules with stronger binding interactions results in drugs that block the binding site - antagonists R M ER Signal transduction 25
- 26. HOW DRUGS ACT l.Enzyme Inhibition: Drugs act within the cell by modifying normal biochemical reactions. Enzyme inhibition may be reversible or non reversible; competitive or non-competitive. 2. Drug-Receptor Interaction: Drugs act on the cell membrane by physical and/or chemical interactions- usually through specific drug receptor sites known to be located on the membrane. Some receptor sites have been identified with specific parts of proteins and nucleic acids. In most cases, the chemical nature of the receptor site remains obscure. 3. Non-specific Interactions: Drugs act exclusively by physical means outside of cells. These sites include external surfaces of skin and gastro-intestinal tract. Drugs also act outside of cell membranes by chemical interactions. Neutralization of stomach acid by antacids is a good example 26
- 27. Receptor Superfamilies • IONCHANNEL RECEPTORS (Iontropic receptor) • G-PROTEIN COUPLED RECEPTORS (Metabotropic R) • KINASE LINKED RECEPTORS • INTRACELLULAR RECEPTORS MEMBRANE BOUND 27
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- 29. Transverse view (nicotinicreceptor) Two ligand binding sites mainly on a-subunits a a g d b Ion channel 2xa, b, g, d subunits Cell membrane a ad b g Binding sites Ion channel receptors (Ligand gated ion channels) 29
- 30. Transverse view (glycinereceptor) Three ligand binding sites on a-subunits a a b b a Ion channel 3xa, 2x b subunits Cell membrane a a a bb Binding sites Ion channel receptors (Ligand gated ion channels) 30
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- 35. • G proteinrefers to any protein which binds to GDP or GTP and act as signal transduction. • G proteins consist of three different subunits (a, b, g- subunit). • a-subunit carries GTPase activity, binding and hydrolysis of GTP. 35
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- 39. Modulate phosphorylation ◦activation of processes ◦ Protein Kinases ◦ Protein Phosphatases Modulate gene expression ◦ transcriptional factors ◦ DNA RNA Proteins ◦ e.g., -R up- or down-regulation ~ 39
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