Receptors as Agonists And Antagonists - Done Flashcards
Define what an agonist is
Mimics the natural messenger and activates receptors - causing a response.
Define what an antagonist is
Drugs that bind to receptors and block but do not activate them, preventing the natural messenger from binding.
What must an agonist design follow?
Drug must have correct binding groups
Binding groups must be correctly positioned
Drug be of correct size for binding site
Why is chirality an important consideration in drug discovery?
The chiral compounds interact differently with enzymes and receptors - think thalidomide disaster
Where possible chirality is avoided
Define pharmacophore
The atoms and functional groups required for a specific pharmacological activity and their relative positions in space.
When chirality is necessary how do chemists get around this? What’s the issue with the other compound?
Asymmetric synthesis is used to only make the active compound
Inactive component - toxicity
What is cortisol and where does it act?
Anti-inflammatory — agonist - glucocorticoid receptor
What is cortivazol and its difference to cortisol? What does the crystal structure show?
Cortivazol has no ketone binding group and has 2 extra rings — agonist
Crystal structure shows different induced fit as new channel opens up, accommodating the extra rings
What do more binding sites mean?
Greater potency - additional binding sites
What is pharmacodynamics the study of?
The study of how molecules interact with targets binding site to produce a pharmacological effect
What is pharmacokinetics the study of?
The study of drug absorption, drug distribution, drug metabolism and drug excretion.
Where does Pilocarpine act and what does it treat?
Muscarinic receptors - agonist
Treats glaucoma
Where does oxotremorine act and what does it treat?
Muscarinic receptors - agonist
Potential Alzheimers treatment
What receptor agonists are used in the treatment of myasthenia gravis?
Nicotinic agonists
What drug is used as an aid to stop smoking?
Varenicline
Where does R-Salbutamol act and what does it treat?
Adrenergic B2 receptor - agonist
Treats asthma
What is the main structural difference between R-Salbutamol and R-Soterenol?
R-Soterenol contains sulphonamide FG
R-Salbutamol contains hydroxymethylene FG instead
Give an example of an opioid analgesic - what’s its use and risks?
Morphine - potent analgesic and sedative
Risks of addiction, tolerance and respiratory depression
Where does morphine act? What does it activate?
Opioid receptor - G-protein coupled receptor activating Gi or Go signal proteins
Give an example of an allosteric modulator for a G-protein coupled receptor
Cinacalcet
(Calcium-sensing receptor)
What does cinacalcet treat?
Thyroid problems
What does cinacalcet mimic and hence enhance the action of?
Mimics the action of endogenous modulators and enhances the action of the natural chemical messenger.
How are antagonist drugs designed to cause no receptor activation?
The drug is a perfect fit - no induced fit
Use of extra binding sites - result in an induced fit that doesn’t activate the receptor
- designed molecule also binds more strongly & prevents natural messenger binding
Give 3 modern techniques used to determine the binding site layout
Genetic engineering - change receptors
X-ray crystallography
Computer based molecular modelling
What is estradiol and what’s its affect?
Steroid hormone
Affects growth and development of a number of tissues
What factor can be exploited in the estrogen receptor?
Very spacious binding pocket - except for region where phenol binds
Once estradiol binds, what proceeds?
H12 lid closes and dimerisation occurs - exposing AF-2 regions
Co-activator binds and transcription begins
How does raloxifene act as an antagonist of the estrogen receptor?
Long side chain blocking Leu540 from coming in
Protonated amino group on side chain forms H-bond to Asp-351 - protrudes from binding site stopping H12 lid closing in
What does raloxifene treat?
Hormone dependent breast cancer
What are serotonin antagonists used as?
CNS active drugs
What are adrenergic antagonists used to treat?
Cardiovascular medicine - beta blockers
What do histamine H2 antagonists treat?
Peptide ulcers and hay-fever
What do estrogen receptor antagonists treat?
Horomone dependent breast cancer
What drug treats ulcers and how does it achieve this?
Cimetidine - H2 antagonist exploiting extra binding sites
Name one a beta blocker, what does it treat and where do they act?
S-Metoprolol -2
S-Betaxolol -2
S-Acebutolol -1
S-Atenolol -1
Treats angina and hypertension - B1 receptors prominent in heart
Where do antidepressants act and how do they work?
At serotonin receptor 5-HT7
-believed to be involved in negative feedback for serotonin release, increasing serotonin levels.
What is the importance of the chlorophenoxy group in serotonin antagonists?
Improves passing blood-brain barrier
Prevents metabolism
What functional groups are key for serotonin antagonists?
Naphthalene ring
Sulphonamide group
Piperidine ring
Name a cholinergic antagonist
Tubocurine
What does tubocurarine do and how does it achieve this?
Muscle relaxant - blocks nerve transmission from nerve to muscle
What is a more unorthodox use of tubocurarine?
Used on arrow heads
How does tubocurarine lock in to the cholinergic receptor?
By binding to acetylcholine site and a nearby cysteine residue.
Two positively charged nitrogens are key in binding.
How do allosteric modulators work?
By binding to an allosteric binding site, causing a conformational change in the active site - shutting it
What is the ‘umbrella’ effect?
Large antagonist molecule binds to a neighbouring binding site, blocking the active site form the messenger.
What 3 explanations can be given to partial agonists?
Ex 1 - agonist may not be causing the IDEAL conformational change, hence receptor effects are reduced
Ex 2 - partial agonist may bind in TWO DIFFERENT WAYS, one way is agonistic and other is antagonistic.
Ex 3 - receptors that bind the same messenger are NOT ALL THE SAME. Partial agonist may be able to distinguish between different receptor types and subtypes
What groups decrease agonism and increase antagonism?
Methyl
Ethyl
Propyl
What group has no agonistic or antagonistic effect on a molecule?
Butyl
What groups increase agonism?
Pentyl and hexyl
What opioid analgesic has 14x the activity of morphine and why?
N-Phenethylmorphine - benzene extension on side chain
(Additional pockets)
Name a partial histamine receptor antagonist
N alpha - Guanylhistamine
(Can reach both binding sites due to size)
What is an inverse agonist?
An inverse agonist is capable of preventing inherent activity of a receptor as well as acting as an antagonist.
What does the existence of inverse agonists suggest?
That receptors don’t have ‘fixed’ inactive conformations but are continually changing shape.
That there is an equilibrium between the active and inactive conformations
What receptors have inherent activity even in the absence of neurotransmitters?
GABA and Serotonin
How can desensitisation occur?
When an agonist binds strongly causing prolonged binging and exposure, so cell reduces synthesis of receptors.
The longer exposure can then cause endocyotsis, where the receptor/drug complex is removed completely from membrane
Phosphorylation can also happen, altering the receptor shape - closing it more permanently
Why is desensitisation a problem?
More drug is required to have same effect - toxicity issues
How does sensitisation occur?
Antagonist is slow to add and slow to leave
Cells synthesise more receptors to compensate for the blocked receptors - known to happen with some Beta blockers
Define tolerance
Higher levels of drug are required to have the same biological response
Define dependence
When a drug is stopped suddenly - withdrawal symptoms - patient tales drug again to stop symptoms
Give an example for both agonist and antagonist therapies for choliergic receptors
Agonist - glaucoma (M)
Antagonist - neuromuscular blockers and muscle relaxants (N)
Give an example of agonist and antagonist therapies for adrenergic receptors
Agonist - anti-asthmatics (B2)
Antagonist - Beta blockers (B1)
Give an example of agonist and antagonist therapies for dopamine receptors
Agonist - Parkinson’s disease
Antagonist - antidepressants (D2/D3)
Give an example of agonist and antagonist therapies for histamine receptors
Agonist - vasodilation
Antagonist - allergies (H1) and anti-ulcer (H2)
Give an example of agonist and antagonist therapies for 5-Hydroxytryptamine receptors
Agonist - anti-migraine (5-HT1D)
Antagonist - anti-depressants (5-HT7)
Name one dopamine receptor antagonist and give its use.
Clozapine
Olanzapine
Risperidone
All clinically effective antipsychotic agents
At what sites do antipsychotic drugs act at? Which is better and why?
Act at D2 and D3 receptors
Blockage of D2 receptors - side effects
D3 antagonists generally have better properties as antipsychotic drugs
Define affinity - and how is it determined?
A measure of how strongly a drug binds to the receptor
Determined by radioligand labelling with a known antagonist
Define efficacy - and how is it determined?
A measure of the maximum biological effect that a drug can produce as a result of a receptor binding.
Determined by measuring the concentration of drug required to produce 50% of maximum possible effect (EC50)
Define potency
The amount of drug required to achieve a defined biological effect
