Exam 4 - Lecture 36, Med chem of Cholinergic Agonists and Acetylcholinesterase Inhibitors

Question 1

Does Acetylcholine have chiral center?

Answer 1

no

Question 2

Cis-isomer Acetylcholine

Answer 2

synperiplanar

Question 3

Trans-isomer Acetylcholine

Answer 3

anticlinal, suggested one that interacts with muscarinic receptors

Question 4

Why is ACh hard to use a drug molecule?

Answer 4

due to ester and quaternary ammonium functional groups

ester = hydrolysis in solution, problem oral route
4th ammonium = good water, bad lipid solubility

Question 5

When methyl group of quaternary nitrogen removed or replaced with larger alkyl groups then….

Answer 5

removed = weak cholinergic agonist
add 1 CH3 = weak cholinergic
add 3 CH3 = cholinergic antagonist

Question 6

Ings rule of 5

Answer 6

no more than 5 atoms between nitrogen and terminal hydrogen atom for maximal muscarinic potency

increasing to longer chain, reduced activity

Question 7

Metacholine challenge test

Answer 7

medical test used to assist in diagnosis of asthma

Question 8

Modification of ethylene bridge

Answer 8

CH3 on alpha = greater nicotinic potency, overall reduced activity

CH3 on beta = greater muscarinic potency, activity equal to ACH

Question 9

CH3 on beta of ethylene bridge isomers

Answer 9

S(+) isomer
slower hydrolysis by AChE compared to acetylcholine

R (-) isomer
weak competitive inhibitor, way less potency than ACH

Question 10

why does methacholne (racemic) produces a longer duration of action than acetylcholine

Answer 10

due to steric hinderance of S isomer, and R is a weak competitive inhibitor of AChE, preventing it from getting to S isomer

Question 11

Why does carbachol and Bethanechol have better bioavailability

Answer 11

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

Question 12

Why cant Pilocarpine gels or tablets or solutions of pilocarpine be stored for longer times?

Answer 12

ring opening and closing occurs, causing epimerization and becomes inactive when stored.

it has good eye permeability but short shelf life

Question 13

Therapeutic applications of AChEIs

Answer 13

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

Question 14

Mechanism of AChE hydrolysis

Answer 14

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)

Question 15

Reversible inhibitors of acetylcholinesterase work by

Answer 15

1. substrate reacts with AChE to form an aclyated enzyme which is more stable than acetylated enzyme but it can still undergo regeneration
2. bind to AChE w/ greater affinity than ACh but don’t react with enzyme substrate (Tacrine and Donepezil HCL)

Question 16

Donepezil HCL

Answer 16

has greater selectivity and longer half life than Tacrine….both short acting, used in Alz

tacrine has hepatotoxicity, this one doesn’t

Question 17

Intermediate-acting reversible inhibitors

Answer 17

regen of carbamylated enzyme much slower than hydrolysis of acetylated enzyme

Question 18

Aryl carbamates

Answer 18

have higher affinity for AChE, and carbamylate it more efficiently than carbamates

Question 19

Rate of carbamylation follows order

Answer 19

carbonic acid ester> methylcarbamic acid esters> dimethylcarbamic acid ester

Question 20

Neostigmine and Pyridostigmine

Answer 20

both orally effective (lack CNS activity) and are commonly used in the treatment of myasthenia gravis

Question 21

Rivastigminetartarate

Answer 21

low hepatotoxicity like donepezil

1 dose can inhibit for up to 10 hrs, classified as intermediate acting (psuedo-irreversible)

Question 22

Irreversible Inhibitors of AChE

Answer 22

leave enzyme esterified as phosphate esters which are very stable

aging plays important role, once aging starts antidote doesn’t do anything

Question 23

Floropryl and Phospholine

Answer 23

one dose can last up to 4 weeks due to aging

used to treat open-angle glaucoma

Question 24

Insecticidal AChEIs

Answer 24

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

Question 25

Antidote Irreversible AChEIs

Answer 25

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