Chapter 8

M M E R 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. R M E R Signal transduction Notes on Drug Design

Design of agonists 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 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 E Agonist R E Agonist R Signal transduction AgonistR Induced fit

van der Waals binding regionH-bond binding region Ionic binding region Binding groups Neurotransmitter O O 2 C H Binding site Receptor Design of a agonist and receptor

O NH 2 Me H H O O 2 C H Binding site Receptor O NH 2 Me H H O O 2 C H Binding site Receptor INDUCED FIT Induced fit allows stronger binding interactions Design of an agonist and receptor

Hypothetical neurotransmitter HO NH 2 Me H Compare Binding groups: Identify important binding interactions in natural messenger Agonists are designed to have functional groups capable of the same interactions Usually require the same number of interactions H-bonding group van der Waals -bonding group Ionic binding group H 2 N NH 2 Me H NHMe HO HO NH 2 Me H H H Me Possible agonists with similar binding groups Design of an agonist

O O 2 C H Binding site Receptor O O 2 C H Binding site Receptor H CH 2 Me H Structure II has 2 of the 3 required binding groups - weak activity H NH 2 Me H II H NH 2 Me H Structure I has one weak binding group - negligible activity Design of an agonist

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 H NH 2 Me OH H O O 2 C H Binding site 2 Interactions only H NH 2 Me H OH No interaction Design of an agonist

One enantiomer of a chiral drug normally binds more effectively than the other Different enantiomers likely to have different biological properties O O 2 C H Binding site 3 interactions O NH 2 Me H H O O 2 C H Binding site 2 interactions OH NH 2 Me H O NH 2 Me H H O MeH 2 N H H Mirror Enantiomers of a chiral molecule Design of an agonist

O N H 2 H H Me CH 3 Agonist must have correct size and shape to fit binding site Groups preventing access are called steric shields or steric blocks No Fit O O 2 C H Binding site CH 3 Steric block Me Steric block Design of an agonist

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 ON H H Me H H O O 2 C H Binding site Perfect Fit (No change in shape)

Design of antagonists OH O 2 C Receptor binding site Extra binding regions

O O Asp - HO Design of antagonists Antagonists can form binding interactions with extra binding regions neighboring the binding site for the natural messenger Extra hydrophobic binding region Hydrophobic binding region Ionic binding region H-bond binding region Hypothetical neurotransmitter

Hydrophobic region O O Asp - HO Design of antagonists Induced fit resulting from binding of the normal messenger Hydrophobic region O O Asp HO - Induced fit

Hydrophobic region O O Asp HO Hydrophobic region HO Initial binding - Design of antagonists Different induced fit resulting from extra binding interaction Hydrophobic region O O Asp HO Different induced fit -

Irreversible antagonists 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 X OH X O Covalent Bond Irreversible antagonism

1 Nu Nu Receptor Propylbenzilylcholine mustard Cl Cl Agonist binding site Antagonist binding site Cl Cl Irreversible antagonists N u Nu Receptor 2 Irreversible binding

Allosteric antagonists 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 ACTIVE SITE (open) ENZYME Receptor Allosteric binding site Binding site (open) ENZYME Receptor Induced fit Binding site unrecognisable Antagonist

Antagonists by the umbrella effect 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 Antagonist Binding site for antagonist Binding site for messenger messenger Receptor

Partial agonists Agents which act as agonists but produce a weaker effect Partial agonist Slight shift Partial opening of an ion channel Receptor O O 2 C H 1 NHMe O H H H O O 2 C 2 NHMe O H H 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

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

Explanation of how drugs affect receptor equilibria A) Resting state B) Addition of agonist C)C)Addition of antagonist D) Addition of inverse agonist E) Addition of partial agonist Inactive conformationsActive conformation Agonist binding site

Desensitization 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 O2CO2C 1 H Ion channel (closed) Agonist NH3NH3

Receptor O H Agonist NH3NH3 O2CO2CDesensitization 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 Induced fit alters protein shapeInduced fit alters protein shape Opens ion channelOpens ion channel

Receptor O H Agonist NH3NH3 O2CO2CDesensitization 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 H Agonist P O2CO2C NH3NH3Desensitization 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 Phosphorylation alters shape Ion channel closes Desensitization

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

Sensitization Antagonist Neurotransmitter Normal response Receptor synthesis No response Response Stop antagonist Excess response No response Increase antagonist Tolerance Receptor synthesis Sensitization Dependence No response

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 Design of an antagonist for the estrogen receptor

Action of the oestrogen receptor Oestradiol H12 Oestrogen receptor Binding site AF-2 regions Dimerisation & exposure of AF-2 regions Coactivator Nuclear transcription factor Coactivator DNA Transcription

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 Design of an antagonist for the estrogen receptor Design of an antagonist for the estrogen receptor

Anticancer agent Tamoxifen as an antagonist for the estrogen receptor