Receptors Flashcards
Why are receptors important?
Drugs that interact with receptors are the most important in medicine
Communication between cells are essential for the body to operate in coordinated and controlled fashion, this is facilitated by chemical messengers
What are the 4 main types of receptors?
Ligand gated ion channels
G protein linked receptors
Tyrosine kinase receptors
Intracellular (cytoplasmic receptors) - not membrane bound
What are receptors?
Protein binding sites on cells whose function is to receive and pass on chemical messages
What are the three main ways the communication process can occur?
1) neurotransmission: nerve cell passes chemical message to another nerve cell
2) hormonal: circulating hormones released from glands are carried by bloodstream to distant organ
3) autacoid transmission: local hormones are released and act on nearby cells
What controls the CNS?
Brain and spinal system which receives and sends messages via a vast network of nerves
What is neurotransmission?
Where the message is transmitted as an electrical pulse which travels down nerve cell towards the target. This can either be a muscle cell or another nerve cell
Do nerve cells connect directly with their targets?
No. There is a gap about 100 Angstrom called the synaptic gap. The electrical pulse is unable to jump
What is released into the synaptic cleft as electrical pulses cannot make the jump?
Neurotransmitters. These are released from the nerve cell and diffuses across the synaptic cleft to the target cell where it binds with a specific receptor protein embedded on the postsynaptical cell membrane
What are the cascade of secondary events resulting from the binding of the neurotransmitter to the post synaptic receptor?
Flow of ions across the cell membrane
Enzymes in target cell switched on or off
What occurs after the cascade of secondary events?
Biological response. This can be the contraction of a muscle cell, increase in blood pressure, increase in heart rate, activation of fat acid metabolism in a fat cell.
What type of proteins are recpetors?
Usually glycoproteins of specific 3D structure and located on the he post synaptic cell membrane
What is the term given to drugs which fit into various types of receptors and elicit a response?
Agonists
What is the term given to drugs which fit into receptors that block the receptor site without initiating response?
Antagonists
What are examples of neurotransmitters that are monoamines?
Acetylcholine Noradrenaline Adrenaline Dopamine Serotonin
What are examples of neurotransmitters which are amino acids?
Glycine
Glutamic acid
γ-aminobutanoic acid
5-hydroxytrptamine
When do we need to interfere with cellular communication?
Too many messengers resulting in overheating of cell. We use an antagonist to reduce these messages back to normal
Not enough messages resulting in a sluggish cell. We use an agonist as a replacement messenger to resume normal cell function
What are examples of drug which alters the sympathetic parasympathetic balance?
Beta adrenergic blockers. These are used to control angina
What is a hormone?
Messenger compounds that are released by the endocrine system
Usually carried in bloodstream to distant cells to exert effect.
E.g. Oxytocin which is released by pituitary gland and acts on uterus and mammary glands. At full term pregnancy, oxytocin initiates the contractions of hue he uterus and induces lactation
What is the region of a receptor that has the correct shape to accommodate the chemical messenger?
The binding site
This differs from an enzyme binding domain as it is the ligand which switches on the receptor. There is also no chemical transformation of the ligand, it leaves unchanged
What actives the signalling process?
The change in shape of the receptor
Which receptors communicate the fastest?
Ligand gated ion channels (fastest)
G protein linked receptors
Tyrosine kinase receptors
Intracellular cytoplasmic receptors for steroid hormones (decreased communication speed)
What is the role of ligand gated ion channel receptors?
Movement of certain ions (Na+, K+) across cell membranes are crucial for nerve function
What is the structure of the ligand gated ion channel receptor?
Composed of up to 5 subunits
Each subunit has 4 transmembrane domains
The centre of complex is hollow, lined with polar amino acids to form a hydrophilic pore.
What happens to the ion channel receptor upon binding of neurotransmitter, hormone or agonist?
Opens ion channel to let ions through
What happens to the ion channel receptor upon binding of atagonist?
Ion channel is prevented from opening
What does the nicotinic acetylcholine receptor do?
Forms Na+ ion channel
Found in neuromuscular junction
Two molecules of ACh are required to open the channel. ACh binds at the α subunit
Why does a small number of neurotransmitters produce a large biological effect?
Opening a few ion channels mobilises thousands of ions for each neurotransmitter involved
What are G protein linked receptors?
Alternative mechanism for transmission of neurotransmitter message.
The protein on the external surface of the cell membrane is linked to an enzyme or ion channel on the surface G proteins
What is the structure of a G protein linked receptor?
Composed of a single subunit which has 7 transmembrane domains,
Binding to receptor results in either enzyme activation or enzyme deactivation
What is the mechanism of G protein linked receptors?
Changes in receptor shape (due to chemical messenger binding) leads to the start up or shut down of enzyme activity,
Likewise, only a small number of neurotransmitters are required to produce large biological effect
What part of the G protein receptor is extracellular?
The n terminus
What part of the G protein is intracellular?
The C terminus
What happens if the fine balance of binding forces of chemical messenger to receptor is strong enough?
It will change the receptor shape which will elicit a response
What happens if the fine balance of binding forces are not strong enough
The chemical messenger will then leave.
What is the pharmacophore approach to drug design?
We have an assumption that the correct positioning of binding groups results in an active chemical messenger (i.e, drug)
The pharmacophore is therefore the spatial arrangement of functional groups that interact with the receptor.
The rest of the molecule is therefore just a framework to hold these functional groups in place
What are the criteria for design of agonists?
Compound must have correct binding groups to except or
Compound must have these groups correctly positioned
Compound must be the right size for the binding site
How important are binding groups?
Very important. If the neurotransmitter or hormone requires 3 binding interactions, our new compound should also have 3 binding sites
The removal of one of her gees would probably result in a significant loss in activity
How important are the positioning of binding groups?
Binding groups must be located in complementary positions to the binding sites in the receptor. If they are in the wrong position, no interaction will occur,
Why are stereogenic centres a warning bell?
Different enantiomer binding can result in disastrous consequences e.g. In the case of thalidomide, one enantiomer was a potent teratogen
Why does the size and shape of the compound need to be considered?
It is possible to have the correct binding groups in the correct positions and still no interaction if it is not the right size and shape.
How do we design an antagonist?
We would design a compound which has similar enough binding properties to the natural chemical messenger to enable it to bind to the receptor, but it must not induce conformational change.
This would ensure no response is achieved.
What is the class of compounds derived from natural sources?
Alkaloids.
These materials contain one or more nitrogen atoms enclosed in a ring system
Which branch of alkaloids have been used as both a recreational and as materials for the treatment of pain?
The opiates
What is the principal alkaloid from crude opium?
Moraine, it is responsible for analgaesic activity
How was morphine discovered? (In 6 stages)
1) recognition that natural plant or herb displays pharmacological action
2) extraction and isolation of active compounds
3) synthetic studies (full and partial synthesis)
4) SAR. Synthesis of analogues to determine the structural requirements needed for activity
5) drug development. Synthesis of more analogues to try and improve activity or reduce side effects
6) theories on nature of the analgaesic receptors. Synthesis of more analogues out test this.
What are the side effects of morphine?
Depression of respiratory centre Constipation Excitation Euphoria Nausea Pupil constriction Tolerance Dependence
What side effects of morphine are useful?
Euphoria used for the terminally ill,
Constipation, used to treat diarrhoea
What are the withdrawal symptoms associated with morphine?
Anorexia Weight loss Pupil dilation Chills Excessive sweats Abdominal cramping Muscle cramps Spasms Hyperirritabilty Lachrymation Tremor Increased BP and HR
What have SAR studies on morphine revealed?
Morphine is rigid. Contains 5 rings and possesses pronounced t shape. A basic N is on the 3° amino group A phenolic (slightly acidic) ring alcohol group aromatic ring ether bridge double bond
What happens if the phenolic OH of morphine is replaced with OCH3?
This forms codeine
Results in 80% loss of activity
There is still a small analgaesic effect, mainly used in anti cough and anti diarrhoea formulations
Codeine is actually a prodrug for morphine. Demethylation takes place in the liver
What happens if the phenolic OH of morphine is replaced with OAc?
Forms 3-acetyl morphine
This has an increased analgesic activity over codeine
What happens if the 6 alcohol of morphing is replaced with an ethyl group?
Forms 6- ethyl morphine
Analgesic effect is greatly improved
What happens if the 6 alcohol of morphine is replaced with an acetyl group?
6-acetyl morphine is formed.
This also results in a greatly improved analgesic effect
What causes the increase in activity of morphine from slight structural alterations?
It arises as a consequence of changes in pharmacokinetics and not as a function of their affinity for the receptor.
What happens if both the 3 and 6 hydroxyls are acetylated?
Leads to formation of diamorphine/heroin.
Both hydroxyl functions are masked and can traverse the bbb easily.
Why is diamorphine or heroin less active than 6-acetylmorphine if it can cross the bbb?
…
How do we know that the 6-OH group is not required for analgesic activity?
Removal of this is beneficial to analgesic activity
What happens if the N is removed from the 3° amine of morphine?
Complete loss of activity occurs.
Both dimethyl and n-oxide quarternary salts show no activity in vivo.
Direct injection of salts into brain results in analgesic activity about that of morphine which indicates that an is essential and that the compound binds to the target receptor as a protonated salt
What happens when the aromatic ring is removed from morphine?
Results in complete loss of activity
What happens if the ether bridge is removed from morphine?
The ether bridge was found out to not be required
What is the effect of the other isomer of morphine?
No activity
What is the general trend of morphine analogue activity in terms of alkyl group size ?
As the size of the alkyl group is increased from Me to Bu, activity drops to 0
Increasing the size still further results in a slight recovery of activity
What is the result of adding a phenethyl group onto the morphine molecule?
A 14x increase in activity
This suggests that the aromatic ring has located a hydrophobic binding pocket
What are the antagonists of morphine?
Nalorphine.
Virtually no analgesic activity but does bind to and acts as an antagonist at 2 of the 3 morphine receptors.
Does nalorphine induce a conformational change?
Not at the 2-receptors needed to elicit the on response.
It is also a partial agonist at the 3rd receptor hence it is a weak analgesic with no side effects
What are the body’s natural painkillers?
Enkephalins and endorphins
These are short polypeptide chains that range in size from 5-33 amino acids for the 15 or so compounds that have been identified.
What is the key structural component of endorphins and enkephalins?
Met or Leu-enkephalin skeleton at their N terminus.
A Tyr is essential for activity
