Module 1 Flashcards
Pre-scientific era: what remedies were used, where were they obtained, and what was the knowledge for them?
Morphine, aspirin, alcohol, cocaine
Natural sources
- Mechanisms unknown
- Side effects not widely recognised
- Structure of the drug and target is unknown
Cocaine in the 19th century: how accessible was it, was it understood, and where was it used?
Uncontrolled, available from grocery stores
Mechanism not understood
Included in patent medicines
What was cocaine used to treat?
Freud said:
- Mental stimulant
- Treatment for digestive
- Disorders
- Appetite stimulant
- Treatment for morphine addiction
- Treatment for asthma
- Aphrodisiac
- Local anaesthetic
The regulation of cocaine as an anaesthetic throughout time
Early 1900s: regulation
- Procaine synthesised 1905 (Einhorn)
- Tetracaine 1941
- Lidocaine 1943
(Cocaine still used though)
What did Paul Ehrlich research and what synthetic drug did he make?
- Research on sleeping sickness
- Tested >900 arsenical compounds
- 1909 #606 tested on syphilis
- Completely effective
- Released 1910: Salvarsan
The three ways that drugs can be discovered
Natural sources (Cocaine, Aspirin)
Synthetically produced (Salvarsan)
Serenpidity (Penicillin)
Pharmacology, pharmacodynamics, and pharmacokinetics: what do they all mean?
- Actions of drugs on living organisms
- The mechanisms of drug action
- The handling of drugs by body use of drugs as scientific tools (?)
What do drugs target and what are the examples of the exceptions?
Proteins
Exceptions:
* Antacids
* Osmotic diuretics (reduce intracranial pressure)
* DNA modifying drugs (cancer therapy)
* Drugs that target membrane lipids (some antibiotics)
Interactions with the exceptions tend to be non-saturable, with little specificity
Relative sizes of drugs and receptors
Drugs are usually quite small (<500 Da) in comparison to the receptors (100s of kDa)
This general rule does not apply to protein-based drugs like monoclonal antibodies
Drug binding domains: what are they, and what issues may arise if mutations occur in this area?
The cavity in the receptor which allows things (like drugs) to bind given that they can attach to and cope with the chemical environment caused by its amino acids
If a mutation occurs affecting only the binding domain, then the general shape and structure of the receptor may be the same, but drugs (and other binders) may not be able to bind and so that function is lost
What does the binding energy of a drug binding to a protein do?
When the drug binds to a receptor, the binding energy released will either be stabilised in a particular conformation or may cause a conformational change
The conformational change of the protein causes the drug’s effect
Protein superfamilies: what are they and what causes their grouping?
Massive groups containing large amounts of proteins
These are grouped together based on similar structure, function, and gene sequence
CNS, muscle, heart, and DRG: what can mutations to sodium channels in these areas cause?
CNS: epilepsy
Muscle: myotonia, paralysis
Heart: rhythm disorders
DRG: insensitivity to pain, chronic pain, or psychological disorders
Target diversity: what is it and how can it be exploited?
Target diversity is an issue as some drugs may bind to two different types of proteins as some proteins are very closely related and have very similar amino acid sequences.
This can be exploited by synthetically altering drugs to not bind to any other proteins
Endogenous
Originating within the organism (hormone, neurotransmitter)
Exogenous
Originating from outside the organism (light, pressure)
Receptor: what is the definition and what are the types?
A receptor is a protein that interacts with an information-carrying stimulus and passes the information into a different form (either affecting the cell or passing the info further)
TRK, NHR, GPCRs, and LGIC
Acetylcholinesterase: is it counted as a receptor?
No, although it binds to acetylcholine, it breaks it down so it counts as an enzyme
RTK: what do they do, what do they bind to, where are they located, how many are there in the human genome, what are examples, and what are the key characteristics?
Receptor tyrosine kinase phosphorylates tyrosine residues in proteins, altering the protein’s effect and causing a specific result to occur
They bind to peptide hormones and growth factors mainly
Transmembrane
58 transmembrane proteins
Insulin receptors
- May exist as monomers but the functional unit is in a dimeric form
LGIC: what do they do, where are they located, what are examples, and what are the key characteristics?
Ligand-gated ionic channels change the membrane potential after two agonists bind to two receptor sites and open the channel
Transmembrane
Nicotinic-acetylcholine receptors
- They are all multisubunit receptors
- Can allow fast signalling
- Several structurally different types
GPCR: what do they do, where are they located, how many are there in the human genome, what are examples, and what are the key characteristics?
G-protein coupled receptors act with paired proteins (G proteins) and use these proteins to influence cell activity via other proteins
Membrane - 7 transmembrane domain structure
The biggest family of receptors - 831 genes
β₂ adrenoreceptors
- Important in olfactory, vision, and nervous system
- Act via G-proteins (cAMP/IP3/PIP₂/PLC)
NHR: what do they do, what do they bind to, where are they located, how many are there in the human genome, what are examples, and what are the key characteristics?
Nuclear hormone receptors are activated when their agonist enters the cell and binds. The NHR then binds to DNA and affects gene expression by transgression or transactivation
Lipid-soluble ligands (ie steroids)
Intracellular locations
48 receptors
Glucocorticoid receptors
- Effects tend to be slower than other receptors (hours to days)
The worldwide effect of GCPRs: how many drugs target them, what are the annual sales of their drug targets, and how many targets are there?
34% of drugs
> $180 billion
170 drug targets
Examples of conditions where drugs target GPCR and the drugs used to treat them
- Depression: Antidepressants (indirectly)
- Schizophrenia, bipolar disorder: antipsychotics (dopamine D2 receptor)
- Asthma: salbutamol (beta 2 AdR)
- Blood pressure: losartan (Cozaar), atenolol
- Glaucoma: pilocarpine (muscarinic receptors)
- Abuse: analgesics (cannabis, heroin, LSD)