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What are the 2 types of optical isomers?
______ isomers are a result of the rotation around single bonds between two atoms
Which form of DES is more active- trans DES or cis DES?
______ are mirror images and a plane of symmetry may exist.
Which enantiomer is primarily used in nature to synthesize proteins (D or L)?
T/F: enantiomers have all the same physical properties except for the direction each rotates plane polarized light
_________ occur when 2 or more optically active centers are present in a molecule (2 chiral centers)
Ephedrine and Psuedoephedrine are diastereomers. Do they have different melting points and solubilities in water?
T/F: most drugs available are diastereomers.
What are all the reasons why stereoisomers display different biological responses?
- active transport carrier systems
- different lipid and water solubilities
- metabolic enzymes are asymmetric
- excretion of the drug
What are some examples of drugs that have been heavily modeled using 3D structures?
- HIV drugs (Invarase, Crixivan, Norvir)
- ACE inhibitors
What technique is explaining why side effects occur, variability in efficacy, and most importantly possible new indications for drugs?
computer molecular modeling
What is a strucural component or functional group of a molecule whose steric, electronic, and solubility characteristics are interchangeable?
What are some examples of acyclic steric isosteres?
- univalent atoms and groups (-methyl, -hydroxyl, -fluoride, -chloride, -bromide, etc)
- bivalent atoms and groups (-oxygen-, -sulfur-, -NH-, -CH2-)
- trivalent (-CH=, -N=)
What are some examples of cyclic steric isosteres?
What is an example of an antibiotic that is a cyclic steric isostere?
- Cefaclor (Ceclor) is a semi-synthetic molecule
- Loracarbef (Lorabid) is totally synthetic and that changes the microbial spectrum it can reach, but it is very expensive
What are the 2 properties of an agonist/stimulant?
- relative potency
- relative efficacy
What kind of drugs are being pushed to be developed because they promise precise control over diseases mediated by G-protein coupled receptors? (type of binding)
The receptor occupancy theory states that the response observed is a function of what?
the # of receptors occupied
A drug + a receptor bind and form a complex that leads to the production of.....?
- agonist effects
- antagonist effects
- conformational changes in the protein or macromolecule
_____ ______ _______ reveal the affinity and effective concentration of a series of drug analogs?
dose response curves
What theory states that the agonist/stimulant activity is proportional to the rate of drug-receptor combo rather than the # of occupied receptors?
The Rate Theory
_____ have a high association rate but a low rate of dissociation?
antagonists (in the rate theory)
Which theory best explains partial agonist or antagonist properties and that small molecule binding produces specific or non-specific conformational perturbations in a macromolecule?
Macromolecular Perturbation theory
Which theory states that a substrate or drug binding to the receptor induces 3D conformational changes in the macromolecule positioning catalytic groups in the correct position to conduct productive chemistry or altering membrane behavior? (ex opens channels for calcium)
Induced-fit theory of enzyme-substrate interaction
___ needs bioactivation to remove the negative modifier?
_______, the active drug, needs metabolic inactivation by removing the positive modifier to eliminate or minimize unwanted systemic effects?
______ contains both negative and positive modifiers where the negative modifier is removed first at the site of action (as in prodrug) and the positive modifier is removed later when reach systemic circulation after its activity (as in antedrug)?
What is drug latentiation?
- the process of purposely designing and synthesizing a molecule that specifically requires "bioactivation" to a pharmacologically active substance
- -an addition to the prodrug definition
Approximately how many marketed prodrugs are activated by hydrolysis?
a compound that contains a structural characteristic required for pcol activity but is NOT susceptible to metabolism?
these compounds are designed and synthesized as active compounds that readily undergo metabolic inactivation to nontoxic products?
Waht are the 5 objectives for improving bioavailability using a prodrug?
- improved aqueous solubility
- improved passive intestinal absorption
- improved transporter-mediated intestinal absorption
- protection against fast metabolism
- tissue selective delivery
drugs that are attached through a metabolically labile chemical linkage to another molecule designated as the "promoiety"?
What are the advantages of carrier-linked prodrugs?
- increased absorption
- injection site pain relief
- elimination of unpleasant taste
- decreased toxicity
- decreased metabolic inactivation
- increased chemical stability
- prolonged or shortened action
What is an example of a carrier-linked prodrug?
chloramphenicol succinate---> chloramphenicol + sodium succinate
What is the most common type of prodrug?
carboxylic acids and alcohols
What two types of beta-lactam antibiotics cause a prodrug esterification problem?
penicillins and cephalosporins
How do we counteract the beta lactam prodrug ester problem?
create a double ester using a carbonate and an ester
What drug uses a double ester to increase absorption and avoid acid catalyzed decomposition?
Vantin (for URI, UTI, gonorrhea)
What is the most common amine derivative used as a prodrug?
Mannich Base prodrug
Why do we not use amines as much for prodrugs?
because the amides derived from amines have a highly stable amide linkage and there is a lack of amidases with selectivity
Where does the 'azo' linkage as a prodrug usually occur in the body?
in the colon
What drug utilizes the azo linkage as a prodrug to its advantage?
Which prodrug forms a formaldehyde as a byproduct to treat chronic UTIs?
methenamine hippurate (Hiprex or Urex)
Which class of prodrugs does not contain a carrier or promoiety?
What is an example of a bioprecursor prodrug that undergoes oxidation?
What is an example of a bioprecursor prodrug that undergoes reduction?
- Mitomycin C (Mutamycin)
- it cross-links DNA and cause the cancerous cells to die
What is an example of a bioprecursor prodrug that undergoes phosphorylation?
- Iodoxuridine (Herplex)
- it inhibits DNA polymerase and causes incorrect base pairing in DNA, killing virus
What are some types of carriers that have been used in chemical delivery of drugs?
- cellular carriers (erythrocytes and leukocytes)
- magnetic control targeting
- implanted mechanical pumps
What do Warfarin, Irinotecan, and Atomoxetine all have in common?
they are all metabolized very differently by every person because of metabolic enzymes present in a specific person
What is a common drug that will enhance metabolism?