Unit 4 - Receptors as Drug targets Flashcards
Where are most receptors found?
Embedded within the cell membrane with part of their structure exposed on the outer surface and part exposed on the inner surface
What do receptors interact with?
Chemical messengers outside the cell
- transmit their message to the inside of the cell
What are the two categories of chemical messengers?
Neurotransmitters - released from nerve cells - neurones Hormones - released from glands
What is an endogenous ligand?
Natural chemical messenger which binds to a specific protein receptor which recognises that particular messenger
What is signal transduction?
The endogenous ligand bind in a binding domain that is exposed on the outer surface of the cell, causing a change in shape which triggers a series of further events affecting other proteins within the cell membrane and the cell cytoplasm
What happens to the binding domain once the message has been received?
The endogenous ligand leaves the binding domain unchanged and the protein returns to its inactive conformation or shape
What effect does a full agonist have?
Produces maximal biological response
Has maximal positive intrinsic activity
- efficacy
What effect does a partial agonist have?
Produces partial maximal biological response compared with full agonist
Has lower efficacy
What effect does an inverse agonist have?
Produces opposite biological response of the endogenous ligand
Negative efficacy
What is a competitive receptor antagonist?
Binds to a receptor at the same site as an endogenous or pharmacological agonist
- blocking agonist binding
- blocking receptor activation
Do not affect agonist activity
- maximal response
Do decrease affinity and potency
Can be reversed by increasing the amount of agonist
What is a non-competitive receptor antagonist?
Bind to the same site as the agonist
Generally irreversible owing to formation of a covalent bond between antagonist and receptor
Reduce the number of receptors available to the agonist
What are allosteric non-competitive receptor antagonists?
Drug binds to an allosteric site on the receptor
- different from where an agonist binds
- primary site
Binding to the allosteric site modifies the conformation of the primary sit
- altered conformation is less responsive to the agonist
What methods are used to help design agonist and antagonists?
X-ray structure of protein-ligand complex Ligand Based Drug Design - LBDD Structure Based Drug Design - SBDD Computer Aided Drug Design - CADD
What is Ligand Based Drug Design?
Don’t know receptor structure
Know ligands
What is Structure Based Drug Design?
Know receptor structure
Don’t know ligands
Give examples of non-polar aliphatic amino acids
Glycine Alanine Valine Proline Leucine Methionine Isoleucine
What type of interactions do non-polar aliphatic amino acids form?
Van de Waals
Hydrophobic interactions
Give examples of non-polar aromatic amino acids
Phenylalanine
Tyrosine
Tryptophan
What type of interactions do non-polar aromatic amino acids form?
Van de Waals
Hydrophobic interactions
pi-pi stacking
Give examples of polar, uncharged amino acids
Serine Threonine Cysteine Aspargine Glutamine
What interactions do polar, uncharged amino acids form?
Hydrogen bonding
Disulphide bonds
- cysteine
Give examples of positively charged (basic) amino acids
Lysine
Arginine
Histidine
What interactions do positively charged (basic) amino acids form?
Ionic interactions
Hydrogen bonds
Give examples of negatively charged (acidic) amino acids
Aspartate
- aspartic acid
Glutamate
- glutamic acid
What interactions do negatively charged (acidic) amino acids form?
Ionic interactions
Hydrogen bonds
What is the active principle of opium?
Morphine
How does morphine work as an effective painkiller?
Acts in the brain
- appears to elevate the pain threshold
- decreasing the brain’s awareness of pain
Give examples of semisynthetic derivatives of morphine
Codeine
Diacetylmorphine
- heroin
Dihydromorphine
What are the uses of codeine?
Mild analgesic
Cough sedative
Why is diacetylmorphine (heroin) addictive?
Fewer side effects so dependence more easily acquired
- don’t suffer the bad parts!
What is dihydromorphine used for?
Relief of mild to moderate pain
Give some examples of synthetic derivatives of morphine
Meperidine
- pethidine
Methadone
How does naloxone work?
Pure narcotic antagonist
- removes
- respiratory depression
- nausea
- hypotension
- analgesia
Does not relieve pain
No potential for addiction
What is naloxone used for?
Used to rapidly reverse effects of opiate overdose
- inhaler
- autoinjector
What is nalorphine?
Antagonist - should not have any analgesic activity BUT weak activity observed Free from side effects Unable to switch on 2 receptors - true antagonist at these receptors - but gives some activity so must be another receptor - nalorphine activates a third receptor - weak or partial agonist
What led to the synthesis of related compounds of naloxone?
Naloxone was almost totally free from side effects
