Exam 4 - Lecture 36, Med chem of Cholinergic Agonists and Acetylcholinesterase Inhibitors Flashcards
Does Acetylcholine have chiral center?
no
Cis-isomer Acetylcholine
synperiplanar
Trans-isomer Acetylcholine
anticlinal, suggested one that interacts with muscarinic receptors
Why is ACh hard to use a drug molecule?
due to ester and quaternary ammonium functional groups
ester = hydrolysis in solution, problem oral route
4th ammonium = good water, bad lipid solubility
When methyl group of quaternary nitrogen removed or replaced with larger alkyl groups then….
removed = weak cholinergic agonist
add 1 CH3 = weak cholinergic
add 3 CH3 = cholinergic antagonist
Ings rule of 5
no more than 5 atoms between nitrogen and terminal hydrogen atom for maximal muscarinic potency
increasing to longer chain, reduced activity
Metacholine challenge test
medical test used to assist in diagnosis of asthma
Modification of ethylene bridge
CH3 on alpha = greater nicotinic potency, overall reduced activity
CH3 on beta = greater muscarinic potency, activity equal to ACH
CH3 on beta of ethylene bridge isomers
S(+) isomer
slower hydrolysis by AChE compared to acetylcholine
R (-) isomer
weak competitive inhibitor, way less potency than ACH
why does methacholne (racemic) produces a longer duration of action than acetylcholine
due to steric hinderance of S isomer, and R is a weak competitive inhibitor of AChE, preventing it from getting to S isomer
Why does carbachol and Bethanechol have better bioavailability
Carbachol has carbamate, impart stability to structure..making hydrolysis take longer
Bethanechol resistant to hydrolysis due to carbamate, and B CH3….longest acting selective for mAChRs…S isomer better binding than R
Why cant Pilocarpine gels or tablets or solutions of pilocarpine be stored for longer times?
ring opening and closing occurs, causing epimerization and becomes inactive when stored.
it has good eye permeability but short shelf life
Therapeutic applications of AChEIs
improve muscle strength in Myasthenia Gravis
decrease intraocular pressure in IOP
treatment symptoms of Alz and similar cognitive disorders characterized by cholinergic deficancey
used as insecticides and chemical warfare agents
Mechanism of AChE hydrolysis
Serine -OH group attack double bond O, and forms transition complex leading to inactive enzyme and left with choline. Enzyme then regenerates itself w/ contact to water
They have 2 sites, anionic (NH2, -) and estaratic ( + charge)
Reversible inhibitors of acetylcholinesterase work by
- substrate reacts with AChE to form an aclyated enzyme which is more stable than acetylated enzyme but it can still undergo regeneration
- bind to AChE w/ greater affinity than ACh but don’t react with enzyme substrate (Tacrine and Donepezil HCL)
Donepezil HCL
has greater selectivity and longer half life than Tacrine….both short acting, used in Alz
tacrine has hepatotoxicity, this one doesn’t
Intermediate-acting reversible inhibitors
regen of carbamylated enzyme much slower than hydrolysis of acetylated enzyme
Aryl carbamates
have higher affinity for AChE, and carbamylate it more efficiently than carbamates
Rate of carbamylation follows order
carbonic acid ester> methylcarbamic acid esters> dimethylcarbamic acid ester
Neostigmine and Pyridostigmine
both orally effective (lack CNS activity) and are commonly used in the treatment of myasthenia gravis
Rivastigminetartarate
low hepatotoxicity like donepezil
1 dose can inhibit for up to 10 hrs, classified as intermediate acting (psuedo-irreversible)
Irreversible Inhibitors of AChE
leave enzyme esterified as phosphate esters which are very stable
aging plays important role, once aging starts antidote doesn’t do anything
Floropryl and Phospholine
one dose can last up to 4 weeks due to aging
used to treat open-angle glaucoma
Insecticidal AChEIs
designed much more specific in nature and aim to target different insect.
exploit microsomal oxidation, becomes very toxic in insects but humans don’t have that mechanism/minimal in nature
S turn to O in insect, not done in humans
Antidote Irreversible AChEIs
before aging starts, give Pralidoxime chloride….gets attracted to - with its + charge, and OH removes compound from enzyme
If aging happens, this won’t work
