SARs of ANS-Cholinergic Agents

• Neurotransmitters:

  1. Acetylcholine
  2. Norepinephrine
  3. Dopamine
  4. Serotonin
  5. GABA (y-aminobutyric acid)
  6. Endorphins
• prototype of Cholinergic Agonists

  Acetylcholine
• Inhibits active uptake of choline

  Hemicholinium
• Inhibits vesicular storage of ACh

  Vesamicol
• Blocks calcium influx

  Botulinum Toxin (Botox)
• Stimulates calcium influx


  Black widow spider toxin
• Black widow spider toxin

  Latrotoxin
• enzyme that metabolized/breaks down ACh

  acetylcholinesterase
• receptor in the CNS, parietal cells


  M1
• receptor in the heart


  M2
• receptor in the GIT, respiratory, smooth muscle, glands, pupil, lacrimal glands, blood vessels


  M3
• receptor in the Skeletal muscles


  Nm
• receptor in the postganglionic neurons


  Nn
• Gq: increases phospholipase C activity


  M1, M3, M5
• Gi: decreases adenylyl cyclase activity and K+ current


  M2, M4
• what type of receptors are muscarinic receptors?


  Metabotropic receptors (type 2)
• what type of receptors are nicotinic receptors?


  Ionotropic receptors (type 1)
• Muscarinic Agonist - Direct Acting (Choline Esters):

  1. Acetylcholine (Miochol-E)
  2. Methacholine (Provocholine)
  3. Carbachol (Miostat)
  4. Bethanechol (Uecholine)
• Domains of Acetylcholine structure:

  1. Quaternary ammonium group (QACs) - "oniums"
  2. Ethylene bridge
  3. Acyloxy group
• Muscarinic Agonist - Direct Acting (Alkaloids):

  1. Pilocarpine (Salagen)
  2. Cevimeline (Evoxac)
  3. Arecoline
  4. Muscarine
• Quaternary Ammonium Group (Onium group)

  1. For optimum cholinergic activity amine group must be quaternary
  2. Primary, secondary, and tertiary amines are less active than quaternary amines.
  3. Substitution of one of the three methyl groups with higher alkyl groups (i.e., ethyl, propyl) makes it less active than ACh, while substitution of H atom diminishes muscarinic activity.
  4. Substitution of all three methyl groups with higher alkyl groups (i.e., ethyl or propyl) makes it antagonist at cholinergic receptors.
  5. The substitution of N (by P, S, As, or Sb atom), decreases the cholinergic activity.
• Quaternary Ammonium Group

  
• Acetylcholine

  
• Methacholine

  
• Carbachol

  
• Bethanechol

  
• Ethylene Bridge

  
• SARs of Ethylene Bridge:

  1. Decreasing (to methyl) or increasing (to propyl) the chain length reduces cholinergic activity.
  2. Introduction of methyl group at alpha (α) position forms acetyl-α-methylcholine, which has more selectivity towards nicotinic receptor than muscarinic.
  3. Introduction of methyl group at beta (β) position forms acetyl-β-methylcholine (Methacholine), which has more selectivity towards muscarinic receptor than nicotinic.
  4. Introduction of alkyl group other than methyl at (α) or (β) positions decreases the cholinergic activity.
• Acyloxy Group

  
• S-enantiomer of Methacholine is equipotent with ACh, while R-enantiomer of Methacholine is less potent than ACh
• SARs of Acyloxy Group:

  1. Oxygen atoms of acyloxy group is responsible for H-bonding with cholinergic receptors.
  2. Conversion of acyloxy group to carbamic acid ester increases cholinergic activity and improve oral stability.
  3. Replacement of acyl group with aromatic or high molecular weight esters makes it antagonist at cholinergic receptors.
• Carbamic acid ester

  
• Increase levels of ACh:

  1. Diarrhea
  2. Urination
  3. Miosis
  4. Bronchoconstriction
  5. Brachy cardia
  6. Emesis
  7. Lacrimation
  8. Salivation
  9. Sweating
• SAR of Anti-muscarinic agents

  
• Nicotine

  
• Trimethaphan

  
• Hexamethonium

  
• Mecamylamine

  
• Substituent R1 = aryl group or carbocyclic group

  Substituent R2 = H atom, hydroxyl, or hydroxymethyl
• Substituent R2 = H atom, hydroxyl, or hydroxymethyl, which increases potency by participating in H-bonding with the receptor.