Hydrolysis
What are cyclic nucleotides & what are they used for?
-intracellular second messengers that play a key role in many physiological processes -they are targets for rational design of family-selective inhibitors as therapeutics to treat those biological disorders
Name the insecticide inhibitors of acetylcholinesterase. 3
-paraoxon -parathion -fensulforthion
Pharmacologic activity of a compound is dependent on what 2 things?
-the rate/affinity by the compound reacts/associates with a receptor or active site of an enzyme (sigma) -lipophilic character of the compound (pi)
How many leaving groups are there in hydrolysis of amides?
1 leaving group
What is the most active anti-cocaine catalytic antibody?
12A10
How many leaving groups are there in carbamate hydrolysis?
2
How many leaving groups are there in carbonate hydrolysis?
2 leaving groups
What happens in direct reaction with a water molecule?
OH attaches to carbonyl carbon & H attaches to OR
What is the second bridging site in the active site of both PDE4 & PDE5?
OH1
What metabolizes cAMP & cGMP?
PDE superfamily
What does PDE does viagra also target that causes side effects?
PDE6
What leads to OP poisoning?
aging
What are PDE5 target drugs now being used to treat?
alzheimer's disease
State the order of the 4 compound stability in water.
amide> carbamate> carbonate> ester>
What 2 drugs target PDE4?
antidepressants & memory enhancers
PDE2 drugs have a promising target for.... 2
anxiolytic drugs & memory enhancers
Name an ex of a carboxylic acid drug.
benzocaine, cocaine
Where is the bond broken in hydrolysis of carbonate?
between the carbonyl carbon & both attached oxygens
Where is the bond broken in hydrolysis of amide?
between the carbonyl carbon & the N group
Where is the bond broken in carbamate hydrolysis?
between the carbonyl carbon & the O & the N
Where is the bond broken in carboxylic acid hydrolysis?
between the carbonyl carbon & the attached oxygen
Where is the bond broken in hydrolysis of phosphate esters?
between the oxygen & the R group
For pH>4, which hydrolysis pathway for cAMP is the most important?
cAMP + OH-
What is the dominant hydrolysis pathway in neutral solution?
catalyzed HO-
The mechanism for the hydrolysis of carbonate should be similar to that of-----
ester
State the hydrolysis rate of the 4 types of hydrolysis.
ester> carbonate> carbamate> amide
T/F: p value is independent of the type of reaction in consideration
false every reaction has it's own p value & can be positive or negative
What is the structure of the nerve agent inhibitors of acetylcholinesterase?
fluorinated phosphates
What has to happen to (-) cocaine before it can be hydrolyzed by BChE?
has to go through rotation
larger pi value= higher/lower pharmacologic activity
higher
What is the process of general base-catalyzed hydrolysis?
hydroxide ion attaches to water which attaches to carbonyl
What is the process of specific base-catalyzed hydrolysis?
hydroxide ion can directly attach to a carbonyl
What drugs target PDE5?
male ED drugs (sildenafil, vardenafil, tadalafil)
How does the catabolic Ab catalyze the hydrolysis of cocaine?
more favorably stabilizing the trasition state during the hydrolysis process
Larger pKa than reference= negative/positive sigma value= substituent is electron donating/withdrawing
negative, donating
hydrolysis of phosphate esters X1=OH, X2=OH. How many times can it hydrolyze?
one time
What is used to treat OP poisoning?
oximes like obidoxime & pralidoxime
For very low pH, which hydrolysis pathway for cAMP is the most important?
pH dependent cAMP + H2O
For pH 2-3, which hydrolysis pathway for cAMP is the most important?
pH independent cAMP + H2O
smaller pKa than reference= negative/positive sigma value= substituent is electron donating/withdrawing
positive, withdrawing
Can BChE catalyze hydrolysis of OP compounds?
possibly, yes chemically be depends on wether the OP compounds fits the BChE active site
Name an example in the body of amide hydrolysis.
protein metabolism
What is the process of general acid-catalyzed hydrolysis?
proton attacks water which attacks the carbonyl
What is the process of specific acid-catalyzed hydrolysis?
proton directly attacks carbonyl
What is a hydrolysis reaction?
reaction in which water reacts with a compound to produce other compounds
What are oximes?
recombinant form of human BChE
Name the 2 factors that affect the sigma parameter.
resonance & inducted effects of the functional group
What happens during a hydrolysis reaction?
splits one chemical bond & the addition of the proton and the hydroxide anion form the water
hydrolysis of phosphate esters X1=OR, X2=OR. How many times can it hydrolyze?
three times
T/F: sigma value is independent of the type of reaction in consideration
true
hydrolysis of phosphate esters X1=OH, X2=OR. How many times can it hydrolyze?
two times
Which form of cocaine is natural & biologically active?
(-) cocaine
OP---> phosphorylates the ........ or ..... --->either ...... or ......
-AChE or BChE -either aging or reactivation
Name the nerve agent inhibitors of acetylcholinesterase. 3
-DFP -sarin -soman
Name an example of some drugs that undergo amide hydrolysis.
-Pen G -Lidocaine
Name the 3 ways that cAMP is hydrolyzed.
-cAMP + OH- -cAMP + H2O pH independent -cAMP + H2O pH dependent
Name the 4 hydrolysis pathways.
-direct reaction with water molecule -base-catalyzed hydrolysis -acid-catalyzed hydrolysis -enzymatic hydrolysis
The hydrolysis of carbamate is similar to the hydrolysis of ---- and -----.
-esters -amides
