Med org 2

• ACETYLCHOLINE


  Prototypical muscarinic and nicotinic agonist
• ACETYLCHOLINE


  • Lack of specificity for nAChRs and mAChRs
  • Undergoes rapid hydrolysis in aqueous solution
• Even if parenterally administered, action is fleeting as a result of hydrolysis by butyrylcholinesterase (or plasma cholinesterase)
• ACETYLCHOLINE


  • Quarternary ammonium group
  • Poorly absorbed across lipid membranes
  • Soluble in water
• STRUCTURE-ACTIVITY RELATIONSHIPS (SARS)


  • Modification of the quarternary ammonium group
  • Modification of the ethylene bridge
  • Modification of the acyloxy group
• Modification of the quarternary ammonium group


  • Replacement by three ethyl groups - Results to a cholinergic antagonist
  • NH2, or NH3 - Leads to successively diminishing muscarinic activity
  • Affords an active compound but much less so than acetylcholine
• Modification of the ethylene bridge

  • Increasing chain length decreases activity
  • Rule of FIVE: There should be no more than five atoms between the nitrogen and the terminal hydrogen atom for maximal muscarinic potency
  • Replacement of hydrogen with alkyl groups larger than methyl leads to less active compounds
  • Methyl group on carbon β affords Acetyl-β-methylcholine (or Methacholine) - Much greater muscarinic potency
  • Methyl group on carbon α affords Acetyl-α-methylcholine - Much greater nicotinic than muscarinic potency
• Modification of the ethylene bridge

  • mAChRs display stereoselectivity for the enantiomers of methacholine
  • S-(+)-methacholine is equipotent with acetylcholine, whereas the R-(-)-enantiomer is approximately 20-fold less potent
  • S-(+) enantiomer is hydrolyzed slowly; R-(-) enantiomer is a weak inhibitor of AChE
• Modification of the acyloxy group

  • When acetyl group is replaced by higher homologs resulting esters are less potent than acetylcholine
  • Replacement of the acetoxy functional group with a functional group resistant to hydrolysis - Synthesis of carbachol (carbamic ester of choline) - a potent cholinergic agonist
  • Esters derived from carbamic acid are referred to as carbamates
  • Carbonyl carbon is less electrophilic and more stable than carboxylate esters to hydrolysis
  • Exhibits greater stability against hydrolysis; thus, administered orally
• Structure activity relationship for muscarinic agonist activity

  • Molecule must possess a nitrogen atom capable of bearing a positive charge, preferably a quaternary ammonium salt
  • For maximum potency, the size of the alkyl groups substituted on the nitrogen should not exceed the size of a methyl group
  • The molecule should have an oxygen atom, preferably an ester-like oxygen, capable of participating in a hydrogen bond
  • There should be a 2-carbon unit between the O2 and N2 atom
• Specific muscarinic agents


  • Methacholine
  • Carbachol
• Ester-like oxygen


  Capable of participating in a hydrogen bond
• The molecule should have an oxygen atom, preferably an ester-like oxygen, capable of participating in a hydrogen bond
• There should be a 2-carbon unit between the O2 and N2 atom
• Specific muscarinic agents


  • Methacholine
  • Carbachol
  • Bethanechol
  • Pilocarpine
  • Cevimeline
• Methacholine chloride (Provocholine®)


  Acetyl β-methacholine, racemic mixture, selective muscarinic agonist with very little activity at nAChRs, S-(+)-enantiomer is more potent, via inhalation for the diagnosis of asthma
• Carbachol chloride (Isopto Carbachol®)


  Carbamate analog of acetylcholine, exhibits affinity for both mAChRs and nAChRs, more resistant to hydrolysis, weak anticholinesterase activity, treatment of glaucoma and induction of miosis
• Bethanechol chloride (Urecholine®)


  Carbamate analog of methacholine, selective for mAChRs, treatment of postsurgical and postpartum urinary retention and abdominal distention, orally administered
• Pilocarpine hydrochloride (Isoptocarpine®)


  Affinity for M3 mAChR, as a tablet, ophthalmic solution and gel, penetrate the eye and miotic of choice for open-angle glaucoma, treatment of xerostomia, Sjogren syndrome and mucositis following chemotherapy
• Open-angle glaucoma has an open drainage angle, while closed-angle glaucoma has a blocked drainage hole
• Pilocarpine undergoes alkali hydrolysis to give a pharmacologically inactive hydroxy acid (pilocarpic acid) and base catalyzed epimerization at C3 in the lactone to give isopilocarpine, an inactive stereoisomer of pilocarpine
• Cevimeline hydrochloride (Evoxac®)


  A nonclassical muscarinic agonist, quinuclidine derivative (M1 agonist in the CNS, M3 in lacrimal and salivary glands), orally for the treatment of xerostomia and Sjogren syndrome, elimination t1/2 of 3 to 5 hours
• Acetylcholinesterase inhibitors


  • Reversible
  • Irreversible
• Inhibition of the rapid hydrolysis by AChE increases the concentration of acetylcholine in the synapse, producing both muscarinic and nicotinic effects
• Acetylcholinesterase inhibitors, also known as anticholinesterases, are indirect cholinomimetics
• Acetylcholinesterase inhibitors


  • Therapeutically used to improve muscle strength in myasthenia gravis
  • Used in open angle glaucoma (through contraction of ciliary muscle and sphincter) to decrease IOP
  • Recently used for the treatment of symptoms of Alzheimer's disease
  • Used extensively as insecticides and as chemical warfare agents
• Acetylcholinesterase-catalyzed hydrolysis of acetylcholine

  1. Forms an acylated enzyme, hence cannot bind to another molecule of acetylcholine

  2. Hydrolysis to regenerate the active form of AChE and acetic acid

  3. If the enzyme is acylated by a functional group (i.e., carbamyl or phosphate) that is more stable toward hydrolysis, enzyme remains inactive for a longer period of time