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

no

synperiplanar

anticlinal, suggested one that interacts with muscarinic receptors

due to ester and quaternary ammonium functional groups ester = hydrolysis in solution, problem oral route 4th ammonium = good water, bad lipid solubility

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

no more than 5 atoms between nitrogen and terminal hydrogen atom for maximal muscarinic potency increasing to longer chain, reduced activity

medical test used to assist in diagnosis of asthma

CH3 on alpha = greater nicotinic potency, overall reduced activity CH3 on beta = greater muscarinic potency, activity equal to ACH

S(+) isomer slower hydrolysis by AChE compared to acetylcholine R (-) isomer weak competitive inhibitor, way less potency than ACH

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

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

ring opening and closing occurs, causing epimerization and becomes inactive when stored. it has good eye permeability but short shelf life

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

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)

• 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)

has greater selectivity and longer half life than Tacrine….both short acting, used in Alz tacrine has hepatotoxicity, this one doesn’t

regen of carbamylated enzyme much slower than hydrolysis of acetylated enzyme

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

carbonic acid ester> methylcarbamic acid esters> dimethylcarbamic acid ester

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

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

leave enzyme esterified as phosphate esters which are very stable aging plays important role, once aging starts antidote doesn’t do anything

one dose can last up to 4 weeks due to aging used to treat open-angle glaucoma

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