Lecture #2 Flashcards
despite aspirin being used foe centuries. when did we discover its mechanism of action?
around the 19th century
describe the alkaloid class:
large and complex groups of cyclins that contain at least one nitrogen atom
how is aspirin able to work?
it is able to covalently release the acidic group and block COX1 / COX2 and this enables the activation of specific enzymes responsible for the anti-inflammatory activity
what is the difference in structure between coding and morphine?
codine has a methyl group → the presence of the methyl reduces the analgesic activity of the molecule by 90%
what is papaverine and what is it used for?
can trigger muscle and blood vessel relaxation - used in cardiovascular diseases to counteract potential heart attacks
what two natural products are used to treat malaria?
quinine and artemisinin
what is the mechanism of action assumed to be for artemisinin?
there is an oxygen-oxygen bond that seems responsible for certain radical scavenger activity and is useful for the treatment of malaria
what are the two main groups of drugs today?
natural products and those derived from natural products
why is it rare nowadays to have a natural product be considered as a chemical starting point for optimization?
- molecules are too complex - complexity may be associated with better specificity, however the downside is that molecules derived from natural products may be too difficult in terms of synthetic transformation
- complexity and decoration of scaffolds - typically natural products are highly hydrophilic which is not idea for oral absorption
what is the quality of the molecule very much dependent on?
the ability of the chemist to give diversity to the synthesized compound
describe the current phenotypical screening:
the characterization of the New Chemical Entity can be performed in animal models or cell based says to see whether they exert a specific biological effect by altering a behavioral phenotype
what does the mechanism of action of NCE require?
a downstream target deconvolution process
what primary screening assay has been used where the HBV is transiently expressed?
EPA-D 38 - a cell line of hepatoblasomta in which it is possible to express HBV
what do target-based assays investigate?
the detailed molecular ligand-target interaction hypothesis
what was the first benzodiazepine tranquilizer drug?
Librium
describe the mechanism of action for benzodiazapines:
these molecules are positive GABA-A modulators, so they are able to increase the frequency of the opening of the ion channel associated to GABA-A (neurotransmitter that is the major inhibitor in neurons), paired with Cl- → they increase the ability of GABA-A to antagonized the excitability of the neurons
what is the first member of the tricyclic family that is mainly used to treat depression but also antipsychotic agent for bipolar disorder and schizophrenia?
Imipramine
what was the model A of drug discovery described as?
the “needle in a haystack” paradigm → based on serendipity and no information about the biological target
what two main drugs were discovered during the model A time period?
benzodiazepines and Imipramine
what years did model A of drug discovery span over?
1950-1970
what were the main issues with model A?
- lack of a sufficient number of molecules with a suitable degree of structural diversity (molecules obtained were too similar to each other)
- compounds were randomly rested in vivo regardless of their chemical structure
- in-vivo animal models were used as the main filter for progression
what were the three major downsides to animals being used as the main filter for progression in model A of drug discovery?
- lack of pharmacokinetic information
- unknown biological mechanisms
- presence of side effects because no one was investing in selectivity
what is cisplatin?
an inorganic compound that is one of the most effective anti-cancer agents particularly for ovarian and testicular tumors
how is cisplatin used?
nosocomial: IV administration as a mono therapy or in combination
