L8 Receptor and other Drug targets Flashcards
Most drugs produce their effects by binding to protein targets (4)
-receptors
– ion channels
– enzymes
– transporters or carrier molecules
Receptors sub-divided into 4 major types
- ion channel receptors
- G protein-coupled receptors
- enzyme-linked receptors
- nuclear receptors
How are superfamilies distiguished
Based on how they transduce a signal
NOT by which stimulates them or the nature of the change in cell function
Receptors within a particular superfamily use similar___ processes and so tend to have similar general ___
transduction
transduction
Ion channel receptors
- Located in the cell membrane
- Collection of proteins form central pore / channel
- No agonist, ion channel closed, no ion flow
(nicotinic acetylcholine receptor) - 4 subunit proteins
- Ions cannot cross the cell membrane
- ACh binding alters ion channel structure and ions flow into the cell
Ion channel receptors (ACh)
ACh binding alters ion channel structure and ions flow into the cell (nicotinic acetylcholine receptor)-NT agonist
Ion channel receptor list
Location: Cell Membrane
Effector: Channels
Respond to: Fast NT
Time scale of action: Milisecond, very fast
Example: Nicotinic acetylcholine receptor
G protein-coupled receptors
Drug attach to GPCR to cause a change in cell function of the g-protein
- has alpha, beta, gamma, GDP
- binds on membrane or extracellularly
- largest superfam of receptors
G protein-coupled receptors list
Location: Cell membrane (7 transmembrane domains)
Effector: Enzyme of channel
Respond to: Hormones, slow NT
TimeSOA: Seconds, fast
Examples: Adrenoceptors and muscarinic acetylcholine receptors
Effector of GPCR
An agonist binds to receptor to activate g-protein and activates the enzyme/channel
g-protein example asthma
Salbutamol, a b2-adrenoceptor agonist relieves bronchospasm in asthma
G proteins info
– intracellular effector systems or 2nd messenger cascades
– guanosine nucleotide binding proteins, GTP and GDP
– comprise 3 subunits (a, b, g)
Main classes of G-alpha proteins
- Ga(s) activates adenylate cyclase
- Ga(i) inhibits adenylate cyclase
- Ga(q) activates phospholipase C
G proteins that link GPCRs to effector proteins to generate intracellular second messengers
– (Gas) adenylate cyclase generates cAMP
– (Gaq) phospholipase C generates inositol trisphosphate and diacylglycerol
GPCR activation: airway smooth muscle
Salbutamol (agon) →
ß2-adrenoceptor →
G(s) (stimulatory GP) →
Adenylate cyclase (transducer/effector protein) →
cyclic amp →
relaxation (effect)
Enzyme-linked receptors list
Location: Cell membrane
Effector: Enzyme
Respond to: Metabolism, growth, differentiation
TimeSOA: Minutes, slow
Examples: insulin receptor, receptors for cytokines, growth factors
Enzyme linked receptor example insulin receptor
In diabetes, insulin is used to activate the insulin receptor, reducing blood glucose levels
insulin receptor
tyrosine kinase → intracellular proteins → stimulate pathway for glucose transport (GLUT4) → translocate
Nuclear Receptors list
Location: Intracellular
Effector: Gene transcription
Respond to: Steroid hormones and other
TimeSOA: Hours, very slow
Examples: Glucocorticoid, other steroid hormones
Glucocorticoid drugs such as prednisolone are effective what agents
Anti-inflammatory
How do drugs reach a nuclear receptor
cross the lipid membrane and bind to it. Receptor stimulation primarily results in altered gene transcription
Nuclear receptors found
inside the cell in either the cytoplasm (Type I) or the nucleus (Type II)
Glucocorticoid receptors are what
type 1 nuclear receptor
Glucocorticoid Receptor agonist
Cortisol is one of the most a common pharmaceutical targets as a endogenous GR agonist.
Protein targets for drug action (4)
Receptors
Ion channels - open for influx or out of ions
Enzymes
Transporters
Agonist and receptors
Agonists bind to and activate receptors and cause transduction
Antagonist and receptors
Will bind but not activate them, rather they prevent an endogenous molecule from binding.
Blocker in ion channels
Blockers physically plug the ion channel. E.g – nifedipine is a Ca2+ channel blocker used to treat hypertension
Modulators in ion channels
Modulators bind to accessory sites and modulate channel activity.
E.g-benzodiazepines enhance GABA-activated Cl- channel opening, used to treat anxiety
Acetylcholine Receptors
There are two families of acetylcholine receptors; muscarinic and nicotinic.
Both families are found pre-synaptically (neurons that send neurotransmitter signals) as well as post-synpatically (neurons that receive neurotransmitter signals).
Enzyme-Linked Receptors effector
protein kinase
In Enzyme-Linked Receptors what do subsrate analogues do
They competitively inhibit the enzyme . E.g - analgesics like paracetamol inhibit cyclooxygenase(block fever and pain)
False substrate in enzymes
Some drugs act as false substrates for enzymes. E.g – anti-cancer drug fluorouracil replaces uracil in purine biosynthesis, blocking DNA synthesis
What is produced when there is a false substrate for enzyme
An abnormal metabolite
Prodrugs and enzymes linked
Prodrugs need to be enzymatically converted to become active. E.g – ciclesonide is converted to the active metabolite in the lung, resulting in fewer adverse effects in non-airways
Specific carrier proteins transport what and where
Specific carrier proteins transport ions and small organic molecules across cell membranes. E.g – glucose, amino acids, neurotransmitters, Na+, Ca2+ etc.
Can some drugs inhibit transporters
fluoxetine
Yes - they will bind to the transporter to block the molecule of interest. E.g – anti-depressant drug fluoxetine inhibits the re-uptake of the neurotransmitter serotonin into neurones
False substrates and transporters
– CNS stimulant amphetamine uses the noradrenaline transporter to enter nerve terminals and replace/release the neurotransmitters noradrenaline and serotonin
False substrates and transporters accumulation
abnormal compound gets to accumulate
Ga(s) protein
activates adenylate cyclase
adenylate cyclase generates cAMP
Ga(i) protein
inhibits adenylate cyclase
Ga(q) protein
activates phospholipase C
– phospholipase C generates inositol trisphosphate and diacylglycerol
