Lecture 11 - Signalling Molecule And Drug Targets Flashcards
What is a ligand?
A signalling molecule that binds to a target/receptor
Are nearly all of the Antagonists endogenous or exogenous?
Exogenous
There are very few endogenous antagonists
What is the pneumonic for the target of signalling molecules/drugs?
RITE
What does the pneumonic for drug targets RITE stand for?
Receptors
Ion channels (Voltage gated)
Transporters
Enzymes
Receptors can be further categorised, what is the pneumonic for these categories?
K(L)ING
What does the pneumonic K(L)ING for the categories of receptors stand for?
Kinase linked receptors
Ion channels (Ligand gated)
Nuclear/intracellular
G Protein Coupled Receptor
How can the activity of an ion channel be changed?
Allosteric phosphorylation
What Voltage gated ion channels are normally targeted by drugs?
VGSCs (Voltage gated sodium channels)
VGCC (Voltage gated calcium channels)
What state are the Voltage gated Sodium channels in when they get blocked by drugs?
Open (Depolarised)
Inactivated
What drug is often used to treat Epilepsy?
Lamotrigine
Phenytoin
How does Lamotrigine help treat epilepsy?
Allows normal levels of CNS by preventing over firing of AP
Blocks the central pores of VGSCs while open or inactive preventing excess Na+ influx
What drug is often used as a local Anaesthetic?
Lidocaine/lignocaine
Bupivacaine (Longer half life than lidocaine)
How does Lidocaine act as a local anaesthetic?
Blocks central pore of VGSCs while open/depolarised or while inactivated
What drug can help treat chronic pain by blocking VGSCs?
Lamotrigine
What Voltage gated ion channels can be targeted by drugs to help treat Hypertension?
Voltage gated Ca2+ Channels (VGCCs)
How does drug blocking of VGCCs on vascular smooth muscle help treat hypertension?
Blocked VGCCs means Reduced Ca2+ influx into cell
Reduced [Ca2+] intracellularly
This means less Ca2+ released for the SR
Smooth muscles of blood vessels relax = Vasodilation
What is a drug which acts to block voltage gated ion channels to treat hypertension?
Amlodopine
What are the key roles of transporters?
Transporting ions and molecules
Setting up and maintaining electrochemical gradients
Important in acting as an energy source for 2º active transport
What is the energy source for 1º active transport?
ATP hydrolysis
What is the energy source for 2º active transport?
Pre established electrochemical gradient (usually established by a Na+/K+ ATPase)
What clinical condition is low synaptic 5-HT levels linked to?
Depression
What is 5-HT also called?
Serotonin
How do Selective Serotonin Re-Uptake Inhibitors (SSRIs) help treat depression?
It reduces the re-uptake of the neurotransmitter serotonin/5-HT
This leads to increased synaptic levels of serotonin/5-HT
What drug is an example of a Selective Serotonin Re-Uptake Inhibitor?
Fluoxetine
What do drugs that treat Diabetes Mellitus target?
SGLT2 (inhibitors)
How does inhibition of the SGLT2 co-transporter in gut cells help treat diabetes Mellitus?
Less glucose absorbed into the blood cells and therefore into the blood reducing glucose intake
What are the 3 possible drugs used to treat Diabetes Mellitus?
Dapagliflozin
Empagliflozin
Metoformin
What is the mechanism of action of Dapagliflozin and Empagliflozin in treating Diabetes Mellitus?
Inhibits the SGLT2 transporters in the gut reducing glucose absorption into the body
What is the mechanism of action for Metformin treating Diabetes Mellitus?
Alters cell metabolism by reducing the amount of Gluconeogenesis performed by hepatocytes
Acts against glucagon
What are the 2 types of ways drugs can act as inhibitors to enzymes?
Directly:
-Competitive inhibitors
-Non-competitive inhibitors
Indirectly:
-Targets receptors that affect enzyme activity
Where do competitive inhibitors bind to an enzyme?
Active site
Where do non-competitive inhibitors bind to an enzyme?
Allosteric site
What type of drugs act as Antihypertensives (treat hypertension) by acting on enzymes?
ACE Inhibitors
What do ACE Inhibitors do?
Reduce conversion of Angiotensin I to Angiotensin II
Less Angiotensin II = Less vasoconstriction and Na+ and water reabsorption
So reduced BP
What are some ACE Inhibitors?
Trandolapril
Captopril
Ramipril
Broadly, what do Tyrosine kinase linked receptors do to other proteins to cause a cell change?
Phosphorylates proteins triggering a phosphorylation cascade
What happens to a Tyrosine kinase linked receptor once a ligand binds to both separate monomers?
Dimer forms (Both monomers come together)
Each monomer Phosphorylates the others Tyrosine residues
Fully phosphorylated = fully active receptor
Phosphorylated tyrosines allow proteins to bind to them and transfer the phosphate to the protein
Phosphorylated protein then goes on in a cascade triggering a cellular change
What hormone is a good example of a hormone that binds to a Tyrosine Kinase receptor?
Insulin
In terms of receptors, what is abnormal about cancer cells?
Have many tyrosine kinase receptors which cause over activation of growth factor
How can Herceptin be used to treat cancer?
Block the Tyrosine kinase receptors preventing the over expression of growth factor