Intermediate Pharmacology (PHAR0009) Notes - Receptors and Signalling
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Course
Intermediate Pharmacology (PHAR0009)
Institution
University College London (UCL)
Explore Intermediate Pharmacology at UCL with a focus on the Receptors and Signalling chapter. Delve into the realm of agonists, drugs, and the intricate structure of receptors. Unravel the complexities of cellular signaling and signal transduction. Please note that these materials are intended for...
Receptors and Signalling – Summary
Introduction
Pharmacology – the study of drugs
o Naming of drugs + targets of drug action + selectivity of drugs + measuring ratio of beneficial to
unwanted effects
Naming drugs
o Classification according to:
Therapeutic use
Molecular mechanism of action
Chemical structure
o Approved name + brand name
Targets of drug action
o Selective toxicity
Drugs bind to other sites of action in addition to main site resulting in unwanted effects
o Magic bullet
Drug might act selectively at intended site of action
Has high affinity for cell – only targets main site by aiming with specific chemicals
Has little effect for organism – minimising damage
Selectivity of drugs
o Pharmacokinetics – drug motion
Study of time course of drug absorption + distribution + metabolism + excretion
Aim to achieve a higher concentration of drug at desired site of action
o Pharmacodynamics – drug power
Study of biochemical and physiological effects of drugs
Design drug to have a higher affinity for desired site of action
o Drug targets
Action at a specific binding site
Specific macromolecular targets may have high affinity for drug + high specificity –
due to stereochemistry of substrate cofactor binding
o Hormone / neurotransmitter receptors – antagonists or agonists
o Enzymes
o Transporters
o Ion channels
o DNA
Action not involving a specific binding site
Drug without identifiable binding site – acts at higher concentrations
o Action of drug is less affected by changes in chemical structure
Measuring ratio of beneficial to unwanted effects of drugs
o Amount of risk acceptable – influenced by severity of medical condition
o Ehrlick’s therapeutic index
Ehrlick’s therapeutic index = maximum non-toxic dose / minimum effective dose
Has difficulties with measurements – due to individual variations to drug
o Therapeutic index – uses better defined doses producing effects in
50% of subjects
Therapeutic index = TD50 / ED50 = toxic dose / effective dose
Dose response curve
o Toxicity
In animal studies – death can be used as a measure of
toxicity
Therapeutic index = LD50 / ED50 = lethal dose / effective dose
, Receptors and Signalling – Summary
Receptor Structure
Receptors = protein involved in mediating the effects of intercellular signalling molecules
o Site of action of: neurotransmitters + hormones + growth factors + other intercellular signalling
molecules
o Four structurally distinct families
Transmembrane receptors
Ligand-gated ion channels (LGICs)
G-protein-coupled receptors (GPCRs)
Kinase-linked and related receptors
Intracellular receptors
Nuclear receptors
Ligand-Gated Ion Channels – LGICs
Ligand-gated ion channels – AKA
o Agonist-activated ion channels
o Neurotransmitter-gated ion channels
o Ionotropic receptors
Structure
o Multi-subunit (oligomeric) transmembrane proteins – contain a central integral ion channel
Multiple subunits co-assemble with each other forming a ring-like structure
Pentameric – 5 complexes
o nAChRs
o GABAARs
o GlyRs
o 5-HT3Rs
Tetrameric – 4 complexes
o GluRs
Trimeric – 3 complexes
o ATP(P2X)Rs
o Extracellular agonist binding site – linked by conformational change to narrow portion of channel
located within lipid bilayer = channel gate
o Neurotransmitter bind to site on extracellular domain causing conformational change opening
integral ion channel (excitatory or inhibitory)
Cation channel = excitatory – causes membrane depolarisation
Acetylcholine (ACh)
o Nicotinic acetylcholine receptor (nAChR)
5-hydroxytryptpamine (5-HT)
o 5-HT(serotonin) type 3 receptor (5-HT3R)
Glutamate (Glu)
o Glutamate receptor (GluR)
Adenosine triphosphate (ATP)
o ATP (P2X) receptor
Anion channel = inhibitory – causes membrane hyperpolarisation
g-aminobutyric acid (GABA)
o GABAA receptor (GABAAR)
Glycine (Gly)
o Glycine receptor (GluR)
o Subunit structure
Pentameric LGICs
Each of the 5 subunits are a single polypeptide
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