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Patrick: An Introduction to Medicinal Chemistry 6e
Chapter 8 RECEPTORS AS DRUG TARGETS Modified
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1. Receptor function Notes
Cell Membrane Receptor message Induced fit Cell Receptor Messenger Cell Messenger Receptor Messenger Message Notes Most receptors are located in the cell membrane Receptors are activated by chemical messengers (neurotransmitters or hormones)
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1. Receptor function Receptors contain a 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
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2. The Binding Site 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 ENZYME
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3. Messenger Binding 3.1 Introduction Notes: Induced fit
Binding site 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
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3. Messenger Binding 3.2 Bonding forces Ionic H-bonding van der Waals
Example vdw interaction Phe H-bond Binding site Ser O H Ionic bond Asp CO2 Receptor
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3. Messenger Binding 3.2 Bonding forces
Induced fit - Binding site alters shape to maximise intermolecular bonding Phe Ser O H Asp CO2 Phe Ser O H Asp CO2 Induced Fit Intermolecular bonds not optimum length for maximum binding strength Intermolecular bond lengths optimised
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4. Overall Process of Receptor/Messenger Interaction
Signal transduction Notes: Binding interactions must be strong enough to hold the messenger sufficiently long for signal transduction to take place Interactions must be weak enough to allow the messenger to depart Implies a fine balance of binding interactions Messengers tend to bind and depart quickly
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4. Overall Process of Receptor/Messenger Interaction
Signal transduction Notes on drug design Agonists are drugs designed to mimic the natural messenger Agonists should bind and leave quickly - number of binding interactions is important Antagonists are drugs designed to block the natural messenger Antagonists tend to have stronger and/or more binding interactions, resulting in a different induced fit such that the receptor is not activated.
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5. Design of Agonists 5.1 Introduction
Agonists mimic the natural messenger of a receptor Agonists bind reversibly to the binding site and produce the same induced fit as the natural messenger - receptor is activated Similar intermolecular bonds formed as with natural messenger Agonists are often similar in structure to the natural messenger E Agonist R E Agonist R Agonist R Induced fit Signal transduction
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5. Design of Agonists 5.2 Requirements
The agonist must have the correct binding groups The binding groups must be correctly positioned to interact with complementary binding regions The drug must have the correct shape to fit the binding site
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5. Design of Agonists 5.3 Example of a hypothetical messenger and receptor H-bond binding region van der Waals binding region Ionic binding region Binding groups Neurotransmitter O 2 C H Binding site Receptor
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5. Design of Agonists 5.3 Example of a hypothetical messenger and receptor O 2 C H Binding site Receptor O N H 2 M e C Binding site Receptor INDUCED FIT O N H 2 M e modoified Induced fit allows stronger binding interactions
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5. Design of Agonists 5.4 Correct binding groups Notes
Ionic bonding group H-bonding group Hypothetical neurotransmitter H O N 2 M e H 2 N M e O Possible agonists with similar binding groups van der Waals bonding group Notes Identify important binding interactions in natural messenger Agonists are designed to have functional groups capable of same interactions Usually require same number of interactions
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5. Design of Agonists 5.4 Correct binding groups II I
H N 2 M e I O 2 C H Binding site Receptor H N 2 M e H C 2 M e Structure I has one weak binding group - negligible activity Structure II has 2 of the 3 required binding groups - weak activity
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5. Design of Agonists 5.5 Correct position of binding groups Notes
2 C H Binding site 2 Interactions only No interaction H NH2Me O H NH2Me OH modified Notes Binding groups must be positioned such that they can interact with complementary binding regions at the same time Example has three binding groups, but only two can bind simultaneously Example will have poor activity
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5. Design of Agonists 5.5 Correct position of binding groups Notes
Mirror O N H 2 M e O M e H 2 N Enantiomers of a chiral molecule O 2 C H Binding site O 2 C H Binding site O N H 2 M e O H N 2 M e 3 Interactions 2 Interactions Notes One enantiomer of a chiral drug normally binds more effectively than the other Different enantiomers likely to have different biological properties
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5. Design of Agonists 5.6 Size and shape Notes
2 C H Binding site O N H 2 Me C 3 C H 3 Steric block No Fit Me Steric block Notes Agonist must have correct size and shape to fit binding site Groups preventing access are called steric shields or steric blocks
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6. Allosteric modulators
Agents which enhance receptor activity by binding to an allosteric binding site rather than the messenger binding site Example 1 Benzodiazepines target the allosteric binding site of the GABAA receptor Example 2 Cinacalcet modified Allosteric modulator for a G-protein coupled receptor called the calcium-sensing receptor Used to treat thyroid problems
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7. Reversible Antagonists
M An An R E R Notes Antagonist binds reversibly to the binding site Intermolecular bonds involved in binding Different induced fit means receptor is not activated The antagonist does not undergo any reaction Level of antagonism depends on strength of antagonist binding and concentration Messenger is blocked from the binding site Increasing the messenger concentration reverses antagonism
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8. Design of Antagonists Antagonists bind to the binding site, but fail to produce the correct induced fit - receptor is not activated Normal messenger is blocked from binding O 2 C H Binding site Perfect Fit (No change in shape) O N H M e modified
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8. Design of Antagonists Antagonists can form binding interactions with binding regions in the binding site not used by the natural messenger OH O 2 C Receptor binding site Extra binding regions
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8. Design of Antagonists Antagonists can form binding interactions with binding regions in the binding site not used by the natural messenger O Asp HO Hydrophobic binding region Extra hydrophobic binding region Hypothetical neurotransmitter H-bond binding region Ionic binding region
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8. Design of Antagonists - -
Induced fit resulting from binding of the normal messenger Hydrophobic region O Asp - HO Hydrophobic region O Asp HO - Induced fit
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8. Design of Antagonists - -
Different induced fit resulting from extra binding interaction Hydrophobic region O Asp HO Initial binding - Hydrophobic region O Asp HO Different induced fit -
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9. Irreversible Antagonists
OH X OH X O Covalent Bond Irreversible antagonism X- Notes Antagonist binds irreversibly to the binding site Different induced fit means that the receptor is not activated Covalent bond is formed between the drug and the receptor Messenger is blocked from the binding site Increasing messenger concentration does not reverse antagonism Often used to label receptors
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9. Irreversible Antagonists
Cl Propylbenzilylcholine mustard 1 N u Receptor N u Receptor 2 Irreversible binding C l Antagonist binding site Agonist binding site
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10. Allosteric Antagonists
(open) ENZYME Receptor Induced fit Binding site unrecognisable Binding site ACTIVE SITE (open) ENZYME Receptor Allosteric binding site Antagonist Notes: Antagonist binds reversibly to an allosteric binding site Intermolecular bonds formed between antagonist and binding site Induced fit alters the shape of the receptor Binding site is distorted and is not recognised by the messenger Increasing messenger concentration does not reverse antagonism modified
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11. Antagonists by the Umbrella Effect
Notes: Antagonist binds reversibly to a neighbouring binding site Intermolecular bonds formed between antagonist and binding site Antagonist overlaps the messenger binding site Messenger is blocked from the binding site Messenger Binding site for antagonist Binding site for messenger Antagonist Receptor Receptor
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12. Partial Agonists Agents which act as agonists but produce a weaker effect Receptor O 2 C H 1 Partial agonist H Receptor O 2 C N M e Slight shift N H M e O Partial opening of an ion channel Possible explanations Agent binds but does not produce the ideal induced fit for maximum effect Agent binds to binding site in two different modes, one where the agent acts as an agonist and one where it acts as an antagonist Agent binds as an agonist to one receptor subtype, but as an antagonist to another receptor subtype
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13. Inverse Agonists Properties shared with antagonists
Bind to receptor binding sites with a different induced fit from the normal messenger Receptor is not activated Normal messenger is blocked from binding to the binding site Properties not shared with antagonists Block any inherent activity related to the receptor (e.g. GABA receptor) Inherent activity = level of activity present in the absence of a chemical messenger Receptors are in an equilibrium between constitutionally active and inactive forms
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14. Explanation of how drugs affect receptor equilibria
A) Resting state Inactive conformations Active conformation Agonist binding site B) Addition of agonist C) Addition of antagonist D) Addition of inverse agonist E) Addition of partial agonist
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15. Desensitization and Sensitization
Receptors become desensititized on long term exposure to agonists Prolonged binding of agonist leads to phosphorylation of receptor Phosphorylated receptor changes shape and is inactivated Dephosphorylation occurs once agonist departs Receptor O O2C 1 H Ion channel (closed) Agonist NH3
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15. Desensitization and Sensitization
Receptors become desensititized on long term exposure to agonists Prolonged binding of agonist leads to phosphorylation of receptor Phosphorylated receptor changes shape and is inactivated Dephosphorylation occurs once agonist departs H O2C O NH3 Agonist Receptor Induced fit alters protein shape Opens ion channel
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15. Desensitization and Sensitization
Receptors become desensititized on long term exposure to agonists Prolonged binding of agonist leads to phosphorylation of receptor Phosphorylated receptor changes shape and is inactivated Dephosphorylation occurs once agonist departs H O2C O NH3 Agonist Receptor
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15. Desensitization and Sensitization
Receptors become desensititized on long term exposure to agonists Prolonged binding of agonist leads to phosphorylation of receptor Phosphorylated receptor changes shape and is inactivated Dephosphorylation occurs once agonist departs H O2C O NH3 Agonist P Receptor Phosphorylation alters shape Ion channel closes Desensitization
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15. Desensitization and Sensitization
Receptors become sensititized on long term exposure to antagonists Cell synthesises more receptors to compensate for blocked receptors Cells become more sensitive to natural messenger Can result in tolerance and dependence Increased doses of antagonist are required to achieve same effect (tolerance) Cells are supersensitive to normal neurotransmitter Causes withdrawal symptoms when antagonist withdrawn Leads to dependence
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15. Desensitization and Sensitization
Neurotransmitter Normal response Antagonist Response No response Receptor synthesis Sensitization Receptor synthesis modified Increase antagonist Tolerance No response Excess response Stop antagonist Dependence
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16. Design of an antagonist for the estrogen receptor
16.1 Action of the estrogen receptor H12 Estrogen receptor Binding site AF-2 regions Dimerization & exposure of AF-2 regions Coactivator Nuclear transcription factor Coactivator DNA Estradiol Transcription
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16. Design of an antagonist for the estrogen receptor
16.2 Binding interactions for estradiol Note Phenol and alcohol of estradiol are important binding groups Binding site is spacious and hydrophobic Phenol group of estradiol is positioned in narrow slot Orientates rest of molecule Acts as agonist
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16. Design of an antagonist for the estrogen receptor
16.3 Binding interactions for raloxifene Note Raloxifene is an antagonist (anticancer agent) Phenol groups mimic phenol and alcohol of estradiol Interaction with Asp-351 is important for antagonist activity Side chain prevents receptor helix H12 folding over as lid AF-2 binding region not revealed Co-activator cannot bind
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16. Design of an antagonist for the estrogen receptor
16.4 Tamoxifen - antagonist for estrogen receptor Anticancer agent
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