Tutorial_cholinergics and anticholinergics

  1. What is the difference in function between sensory and motor neurons of peripheral nervous system?
  2. Nicotinic receptors are of ligand-gated ion channels which is activated faster than GPCR. Which of the following muscles has neuromuscular junctions which contain nicotinic receptors, smooth muscles (involuntary) or striated muscles ( voluntary)
  3. Why nicotinic receptors blockers and not muscarinic receptor blockers are used to relax voluntary muscular contraction (answer similar to above)
  4. My muscarinic receptors blockers are used to relax smooth (involuntary) muscles but not striated (voluntary) muscles?
  5. What is neuronal synapse?
  6. Mention names of two chemical neurotransmitters?
  7. Which neurotransmitter is released at the synapse for both sympathetic and parasympathetic nervous systems?
  8. Which neurotransmitter is released at neuromuscular junctions for parasympathetic nervous system?
  9. Which neurotransmitter is released at neuromuscular junctions for sympathetic nervous system?
  10. What are the clinical effects of activating cholinergic receptors?
  11. What are the clinical effects of activating adrenergic receptors?
  12. The postsynaptic receptor of neurotransmitter is usually enzyme or switch?
  13. Which type of switches is usually present in presynaptic neurons?
  14. Which type of switches is usually present in neuromuscular junctions for sympathetic system?
  15. Which type of switches is usually present in neuromuscular junctions for parasympathetic system?
  16. Mention three types of receptors present in presynaptic neurons which control the release of acetylcholine in cholinergic neurons.
  17. Mention two different types of targets present at the synaptic junction in cholinergic neurons?
  18. Mention at least four features that should be present in a compound to act as cholinergic agonist (i.e. can bind to acetylcholine receptors)
  19. Is it possible for the compound to act as cholinergic agonist without presence of ionized nitrogen (positively charged)? Why?
  20. Two parts:

a) Which of the following compound is active as cholinergic agonist and why?

b) does it means that the compounds which are not active as agonist can be considered as antagonists? why? (Answer is no, but why?)

  1. Define what we mean by SAR?
  2. Not all cholinergic receptors are identical. There are two types of cholinergic receptors. What are they? What are the structural differences between them? How many molecules of acetylcholine is required to activate each one of them? In which type of muscles each one is present?
  3. Why acetylcholine is active against both nicotinic and muscarinic receptors while nicotine is only active on nicotinic receptors and muscarine is only active on muscarinic receptors?
  4. The lower flexibility of muscarine provides selectivity for muscarinic receptors due to the stabilization of the distance between charged nitrogen and ester oxygen to not more than 4.4 Å. Describe how lower flexibility of muscarine is beneficial in increasing the affinity to receptor?
  5. Which of the two receptors has wider spectrum of second messenger tree in the cell, nicotinic or muscarinic and why?
  6. Draw a schematic representation of muscarininc receptor binding pocket, and mention the possible interactions with acetylcholine (without giving names of amino acids involved)
  7. Why only one of the three alkyl substitution at the quaternary nitrogen of acetylcholine can be replaced by ethylene?
  8. Acetylcholine is an endogenous agonist for cholinergic receptor; however, it finds lower medical use, why?
  9. Mention two advantages and two disadvantages of using muscarine (or nicotine) as drugs?
  10. Why acetylcholine is unstable toward water and esterase?
  11. Mention two different approaches to increase the stability of acetylcholine to water and esterase?
  12. The following compound is an analogue of acetylcholine but it is stable toward water and esterase.

a) Discuss the approach being used to provide the stability?

b) Discuss how the approach affects the selectivity of the compound toward the two types of cholinergic receptors (muscarinic and nicotinic receptors)

  1. the next structure is for acetylcholine agonist. Please provides the reason for each of the following features

-  Higher oral bioavailability (low metabolism by intestinal esterases)

-  Higher selectivity for muscarinic receptors.

  1. Pilocarpine is a selective muscarinic receptor agonist. What properties does pilocarpine have in order to be selective muscarinic receptor agonist?
  2. Which of the following compounds is active as selective nicotinic agonist?
  1. Describe the cloth-pin theory for the difference between muscarinic receptor agonist and antagonists?
  2. The cloth-pin theory can be applied to which types of receptors; ligand-gated ion channels or G-protein coupled receptrors?
  3. Mention two structural requirements for the compound to be pure antagonist against nicotinic receptor?
  4. Acetylcholine is unstable to acid and esterase, thus not oral bioavailable. Mention two different methods to increase the stability of acetylcholine
  1. Mention at least two determinants for the antagonistic activity of atropine?
  2. What is the reason of CNS side effects of atropine and how it can be reduced?
  1. Only one of the following muscarinic antagonist is inactive . Describe which one is it? And why others are active?
  1. Only one of the following acetylcholine analogues is active as agonist. Describe which one is it? And why others are not active?
  1. According to Log P value, explain which of the following compounds is expected to have higher incidence of CNS side effects?

Log P = -3 Log P= 0.5

  1. Why the pointed asymmetric center of atropine is easily racemized?
  1. It is said that atropine has an address part (which direct the molecule toward cholinergic receptor) and a message part (which tell the receptor to be OFF). Please shade the two parts using the provide atropine structure:
  1. Please define the message and address theory for ligands acting on GPCRs?
  2. What is the pharmacophore which represent the message and address theory for muscarinic receptor antagonists?
  3. Which of the following two compounds is active as muscarinic receptor antagonist? And why?

  1. To which class of drug target the nicotinic receptors belong?
  2. How many acetylcholine binding sites is present in nicotinic receptor?
  3. What makes decamethonium able to bind nicotinic receptor? Is it the presence of two quaternary amine linked by a linker which spans the two acetylcholine binding sites in the receptor?
  4. Decamethonium has no ester bond, is it the reason behind its long duration of action? Please explain?
  5. Why suxamethonium has shorter half-life than decamethonium?
  1. Why tubucurarine only blocks neuromuscular junctions of voluntary muscles? Is because it is a selective nicotinic receptor antagonist and nicotinic receptors are only present at neuromuscular junctions of voluntary muscles?
  2. Why the distance between the charged nitrogen atoms in nicotinic receptor antagonist is important for activity?
  3. Atracurium is preferred over pancuronium in avoiding the inter-individual variation of half-life. How?
  4. Atracurium can be degraded by two pathways; enzymatically (different among individuals) and non-enzymatically (almost equivalent among individuals). Please discuss each of the two pathways?
  5. Why inverse agonists at nicotinic receptors may have antagonistic effect on muscarinic receptors?
  6. It is said that the concentration of acetylcholine estrase is stable at the synaptic space. How you can rationalize this in term of signal transduction?
  7. It is said that the concentration of acetylcholine estrase is stable at the synaptic space. How the enzyme units are trapped within the synaptic space?
  8. Draw the equation of hydrolysis of acetylcholine by acetylcholine estrase.
  9. Draw a schematic representation for the catalytic amino acids at acetylcholine binding site and how they activate acetylcholine hydrolysis.
  10. For a compound to act as acetylcholine estrase inhibitor, it should have similarity to Ach (thus able to bind the active site) and have electron feeding group to stabilize the transient ester bond. Please explain it schematically.
  11. Mention two important classes of Ach estrase inhibitors known up to date.
  12. Why miotine can inhibit Ach estrase in brain and periphery while neostigmine and pyridostigmine inhibit Ach estrase in periphery only?
  13. Why miotine have shorter half-life compared to neostigmine and pyridostigmine ?
  14. Organophosphorus compounds can also form strong bond with Serine residue of Ach estrase. However the bond is much stronger than that of carbamates. Please describe the difference in their interaction with Ach estrase.
  15. Parathione is used as less toxic insecticide to treat head lice. Why it is not toxic as other organosphosphorous compounds?
  16. Pralidoxime is used as antidote to treat intoxication by organophosphorus compound. It seems that pralidoxime is able to destroy the P-O bond between organophosphorus compounds and Serine reside of Ach estrase better than water. In other word pralidoxime is better nucleophile than water. Which part of pralidoxime is the nucleophile ?
  17. Why pralidoxime has quaternary amine similar to acetylcholine? And how this feature help to reduce the toxicity of pralidoxime?
  18. Why pro-pralidoxime can be used to treat CNS intoxication by organophosphorus compounds while pralidoxime cannot?
  19. The important pharmacophores that should be present in a compound to act as antidote for organophosphorus compounds are having (1) strong nucleophile (like hydroxylamine) which is oriented toward the serine residue by (2) a quaternary amine which mimic choline part of acetylcholine. Is it right? Yes.
  20. Why