Drug receptor Interactions - lecture 6 Flashcards
Name the 5 main models to explain the effects of partial agonists, full agonists and antagonsists.
Occupancy Model, Rate Model, Induction Model, Perturbation Model and Cooperativity Model.
Occupancy Model
The intensity of pharmacological effect is directly proportional to the number of receptor binding sites occupied by the drug.
Rate Model
The intensity of pharmacological effect is directly proportional to the total number of encounters of the drug with its receptor binding sites per unit time.
Induction Model
The pharmacological effect is induced by the drug through specific conformational changes in the active binding site of the receptor complex.
Perturbation Model
Pharmacological substances induce macromolecular perturbations, agonist trigger relatively specific conformational changes as compared to antagonists.
Cooperativity Model
If pharmacological receptors exist in a dynamic equilibrium between activated and inactive states, agonists may shift the equilibrium to an active state and antagonists to an inactive state.
How many receptor super-families are there and what do they provide?
- 4 receptors
- Provides a useful framework for interpreting most drug-receptor interactions.
What are the type 1 receptors and give an example.
Ionotropic receptor
- Ligand-gated ion channel receptor
- example: nAChR
Describe the components of the Ligand-gated ion channel
- Ligand binding domain
- Ion channel lining domain
- Membrane-spanning domain
> Hydrophobic a-helical region
> approx. 20 AAs long
How many subunits are formed together to result in a ion channel complex?
five
Characteristics of type 1 receptors?
- Extremely fast response (milliseconds)
- Membrane-bound
- Direct coupling to ion channel
- Oligomeric assembly of subunits surrounding central ion pore.
What are the type 2 receptors and give an example.
Metabotropic receptor
- G-protein coupled receptor
- example: mAChR
Describe the components of the type 2 receptors
- Ligand binding domains
- G-protein coupling domain
Characteristics of type 2 receptors?
- fast response (seconds)
- membrane-bound
- indirect coupling via G-protein to effector (enzyme or ion channel)
- monomeric assembly comprising of seven trans-membrane helices.
What are the type 3 receptors and give an example.
Kinase-linked receptor
- Cytokine receptor
-example: Insulin-R
Describe the components of the type 3 receptors
- Extracellular Ligand binding domain
- Intracellular, Catalytic domain, Kinase activity
Characteristics of type 3 receptors?
- slow response (hours)
-membrane-bound - direct coupling to enzyme
- single trans-membrane helix
- direct linkage between receptor and kinase enzyme.
What are the type 4 receptors and give an example.
Nuclear receptor
- example: Steroid-R
Describe the components of the type 4 receptors
- Receptor binding domain
- ‘Zinc-fingers’ DNA-binding domain
Characteristics of type 4 receptors?
- slow response (hours)
- intracellular
- coupling via DNA
- effect on gene transcription
- monomeric structure with separate receptor and DNA binding domains
What are the types of nuclear receptors?
Class I, Hybrid Class and Class II
Class 1 of nuclear receptors characteristics and examples?
- present in cytoplasm
- operate as homodimers
- mainly endocrine ligands
- high affinity
examples: GR, MR, ER and PR
Hybrid Class characteristics and examples?
- mainly endocrine
- operates as RXR heterodimers
examples: TR, VDR
Class II characteristics and examples?
- present in nucleus
- operate as heterodimers (except RXR)
- mainly lipid ligands
- low affinity
examples: PPAR, LXR, FXR and RXR
What is the agonist for the nAChR receptor?
Nicotine
Nicotine
- alkaloid from tobacco plants
- Agonist of nicotinic acetylcholine receptor
- stimulating drug (Parasympathomimetic)
- potential toxic side effects
What is the agonist for the beta-adrenoreceptor receptor?
Isoprenaline
Isoprenaline
- B-adrenergic agonist
- structural similarity to adrenaline
- treatment of slow heart rate (Bradycardia)
What is the modulator for the ion channel: Voltage-dep. Na+ - channel?
Lidocaine
Lidocaine
- local anaesthetic
- common usage: injected for dental anesthesia and minor surgery, topical form relieves skin inflammation.
What is the agonist for the Voltage-dep. Ca2+ - channel?
Nifedipine
Nifedipine
- Dihydropyridine
- L-type calcium channel blocker
- Usage:
> anti-anginal drug
> antihypertensive agent
What is the inhibitor for the enzyme: Acetylcholinesterase?
Neostigmine
Neostigmine
- Reversible inhibitor of acetylcholinesterase
- Interference with the breakdown of physiological ligand
- Indirect stimulation of nicotine and muscarinic receptors
- usage:
> Reversal of the effected of non-depolarising muscle relxants following anaesthesia
> Treatment of myasthenia gravis to increase NMJ stimulation.
What is the inhibitor for the enzyme Cyclooxygenase?
Aspirin
Aspirin
- Non-steroidal anti-inflammatory drug (NSAID)
- Inhibitor of the enzyme cyclooxygenase (COX-1>COX-2)
- Usage:
> Analgesic
> Anti-platelet drug
What is the inhibitor for the choline carrier?
Hemicholinium
Hemicholinium
- blocks choline uptake
- not used clinically
- neuromuscular blocking drug
What is the inhibitor for the Na+/K+- pump?
Ouabain
Ouabain
- Cardiac glycoside
- Blocker of Na+/K+ - ATPase
- Increases (Ca2+)i due to decreased NCX
- Therapeutic usage in heart failure
- Potential toxicity
