Muscarinic Activity and AChE Inhibitors
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Questions and Answers

What is a requirement for a compound to have muscarinic activity based on the quaternary ammonium structure?

  • It must have a positive charge at the nitrogen atom. (correct)
  • It must contain only one methyl group.
  • It needs to be an analogue with a hydrogen bond.
  • It should have three ethyl groups on the nitrogen.

    • According to Ing's Rule of Five, what is the maximum number of atoms permitted between the nitrogen and the terminal hydrogen for effective muscarinic potency?

  • Two atoms
  • Four atoms
  • Six atoms
  • Five atoms (correct)

    • What happens to the muscarinic activity of ACh analogues as the length of the carbon chain is increased?

  • Muscarinic activity decreases. (correct)
  • Muscarinic activity remains unchanged.
  • Muscarinic activity increases significantly.
  • Only nicotinic activity is affected.

    • What is the effect of replacing all three methyl groups on the nitrogen with ethyl groups?

    <p>It creates a cholinergic antagonist.</p> Signup and view all the answers

    Which compound is equipotent to ACh on muscarinic receptors?

    <p>Acetyl-β-methylcholine</p> Signup and view all the answers

    Which type of AChE inhibitor is characterized by a slower regeneration compared to acetylated enzymes?

    <p>Reversible AChEIs</p> Signup and view all the answers

    What structural feature makes physostigmine more effective in crossing the blood-brain barrier (BBB)?

    <p>It is a tertiary amine.</p> Signup and view all the answers

    Which statement accurately reflects the stability of the acetylated enzyme and the carbamylated enzyme?

    <p>The carbamylated enzyme is less stable than the acetylated enzyme.</p> Signup and view all the answers

    Which of the following AChE inhibitors has the strongest inhibition due to better affinity?

    <p>Physostigmine</p> Signup and view all the answers

    What type of metabolism is observed in neostigmine and pyridostigmine?

    <p>Analogue to acetylcholine metabolism</p> Signup and view all the answers

    Which carbamate is characterized by a quarternary ammonium salt and does not cross the BBB?

    <p>Neostigmine</p> Signup and view all the answers

    What is the primary mechanism of action for reversible AChE inhibitors?

    <p>Carbamylation of the serine residue</p> Signup and view all the answers

    Which substance is not considered an aryl carbamate?

    <p>Carbachol</p> Signup and view all the answers

    What is the primary purpose of antispasmodics in the context of smooth muscle spasms?

    <p>To reduce spasms of GI and urinary smooth muscles</p> Signup and view all the answers

    Which of the following correctly describes a key characteristic of muscarinic receptors?

    <p>They are activated by acetylcholine (ACh).</p> Signup and view all the answers

    What component is essential for the synthesis of acetylcholine in cholinergic neurons?

    <p>Acetyl coenzyme A</p> Signup and view all the answers

    What is the main role of acetylcholinesterase (AChE) in the synaptic space?

    <p>To hydrolyze free ACh and terminate its action</p> Signup and view all the answers

    Which of the following statements is incorrect regarding muscarinic receptor agonists?

    <p>Defined stereochemistry is not important for interaction.</p> Signup and view all the answers

    Why have therapeutic agents targeting ACh biosynthesis not been successful?

    <p>The synthesis of ACh is not directly controllable.</p> Signup and view all the answers

    Which two types of bonds are primarily involved in the interaction of muscarinic receptor agonists at the receptor sites?

    <p>Ionic and hydrogen bonds</p> Signup and view all the answers

    Which receptor type is primarily involved in myasthenia gravis?

    <p>Nicotinic receptors</p> Signup and view all the answers

    What type of nitrogen is associated with better absorption and distribution of anticholinergic agents?

    <p>Tertiary nitrogen</p> Signup and view all the answers

    What alkyl chain length is typically associated with the most potent anticholinergic agents?

    <p>2-4 carbons</p> Signup and view all the answers

    Which of the following factors enhance the ability of antagonists to outcompete acetylcholine?

    <p>Added sterics</p> Signup and view all the answers

    What is the main mechanism of action for irreversible AChE inhibitors?

    <p>Forming phosphate esters with the enzyme</p> Signup and view all the answers

    Why are irreversible AChE inhibitors referred to as irreversible?

    <p>They form stable phosphate esters that cannot be hydrolyzed quickly.</p> Signup and view all the answers

    Which of the following statements regarding quaternary ammonium compounds is true?

    <p>They have a high ionic character.</p> Signup and view all the answers

    In PJ's case, which treatment is the physician likely considering to counter anticholinergic overdose?

    <p>Administering a cholinergic agonist</p> Signup and view all the answers

    What is one of the primary therapeutic uses of muscarinic antagonists?

    <p>Treating smooth muscle spasms</p> Signup and view all the answers

    Which functional groups in the SAR of muscarinic antagonists are most potent?

    <p>Hydroxyl and hydroxymethyl groups</p> Signup and view all the answers

    What pharmacological role do antagonists play in relation to agonists?

    <p>They compete with agonists for receptor binding.</p> Signup and view all the answers

    Why might tertiary amines be favored in certain medications over quaternary ammonium salts?

    <p>They are better absorbed through all administration routes.</p> Signup and view all the answers

    What is a key characteristic of muscarinic antagonists?

    <p>They act as competitive antagonists of acetylcholine.</p> Signup and view all the answers

    What is the role of gastric lavage in PJ's treatment plan following anticholinergic overdose?

    <p>To remove toxic substances from the stomach.</p> Signup and view all the answers

    What type of agents are commonly used in warfare and insecticides?

    <p>Irreversible AChE inhibitors</p> Signup and view all the answers

    What is the significance of the structural model provided by atropine in drug design?

    <p>It has guided the design of muscarinic antagonists by resembling ACh.</p> Signup and view all the answers

    Which of the following best describes the rate of hydrolysis for the phosphorylated enzyme compared to the carbamylated enzyme?

    <p>The phosphorylated enzyme hydrolyzes significantly slower.</p> Signup and view all the answers

    Which statement accurately describes the pharmacological properties of Methacholine Chloride?

    <p>Its S-enantiomer is significantly more potent than the R-enantiomer.</p> Signup and view all the answers

    What characteristic of Carbachol Chloride contributes to its longer duration of action?

    <p>It is resistant to enzyme-catalyzed hydrolysis.</p> Signup and view all the answers

    Which functional characteristic is unique to Bethanechol Chloride compared to other drugs?

    <p>It selectively activates only muscarinic receptors.</p> Signup and view all the answers

    What is a common indication for AChE inhibitors?

    <p>Myasthenia gravis.</p> Signup and view all the answers

    What distinguishes Pilocarpine from other muscarinic agonists?

    <p>It does not adhere to traditional SAR principles.</p> Signup and view all the answers

    Which feature of Cevimeline HCl allows for its function as a muscarinic antagonist?

    <p>It is derived from quinuclidine.</p> Signup and view all the answers

    How does the mechanism of AChE inhibitors increase cholinergic effects?

    <p>By prolonging the presence of ACh in the synapse.</p> Signup and view all the answers

    What is the primary role of AChE in cholinergic neurotransmission?

    <p>To rapidly hydrolyze ACh after neurotransmission.</p> Signup and view all the answers

    Study Notes

    Drugs Affecting Cholinergic Neurotransmission

    • Cholinergic neurons release acetylcholine (ACh)
    • Cholinergic receptors are found in the autonomic nervous system (parasympathetic and sympathetic), somatic nervous system, and some CNS neurons.
    • Cholinergic receptors are either muscarinic or nicotinic, based on their ability to bind muscarine or nicotine, respectively.

    Introduction to Acetylcholine (ACh)

    • Neurons releasing acetylcholine are called cholinergic.
    • Cholinergic neurons are present in the autonomic (parasympathetic and sympathetic), somatic, and a few CNS neurons.
    • ACh receptors are either muscarinic or nicotinic types.

    Functions of Acetylcholine (ACh)

    • Parasympathetic nerve impulses induce smooth muscle contraction in the GI and urinary tracts, contract the ciliary muscles of the eye and relax the blood vessels and heart.
    • This function is associated with "Rest and Digest" activity.

    Classes of Drugs

    • Cholinomimetic (parasympathomimetic) agents stimulate the parasympathetic nervous system.
      • These include agonists of cholinergic receptors and inhibitors of acetylcholinesterase (AChE).
    • Cholinolytic (parasympatholytic) agents have an affinity for cholinergic receptors but no intrinsic activity.
      • These are cholinergic antagonists.

    Introduction, Continued

    • ACh deficiencies can lead to several diseases; however, directly administering ACh is not an effective treatment.
    • Direct ACh administration can cause non-selective effects and potentially severe adverse effects.

    Indications for Cholinergic Agonists and Antagonists

    • Muscarinic Cholinergic Agents (Agonists):
      • Post-surgical use to reestablish smooth muscle tone.
      • Glaucoma treatment
      • Potential cognitive disorder treatment (such as Alzheimer's disease).
    • Muscarinic Antagonists (Anticholinergics):
      • Reducing smooth muscle spasms due to overstimulation (e.g., GI and urinary tract spasms).
      • Overactive bladder treatment.

    Muscarinic Acetylcholine Receptor Subtypes

    • Receptors vary in location and cellular response, affecting various functions like cognition, seizures, secretions, and autonomic ganglia.
    • Differences exist in their ability to affect heart rate, smooth muscle, and other functions. There is a lack of highly selective antagonists, making selective treatment difficult.

    Muscarinic Receptors are GPCRs

    • ACh causes the dissociation of G-protein, leading to intracellular second messenger responses (e.g., cAMP, cGMP, IP3, DAG, arachidonic acid, and Ca2+).

    Overview of GPCR Signaling

    • The process of activation and deactivation of G proteins, involving GTP and GDP exchange.

    Nicotinic Receptor

    • Nicotinic receptors are present in the skeletal neuromuscular junction, adrenal medulla, and autonomic ganglia, linked to myasthenia gravis (an autoimmune disease).
    • These receptors function as ligand-gated ion channels for Na+ and K+, enabling ion passage.

    Acetylcholine Neurochemistry

    • ACh is synthesized in cholinergic neurons by transferring acetyl from acetyl coenzyme A to choline.
    • Choline is acquired from serine and from hydrolysis of ACh by AChE.
    • Free ACh is rapidly hydrolyzed by AChE
    • This process stops the effect of ACh.

    SAR and Drug Design

    • Understanding structure-activity relationships (SAR) of acetylcholine and cholinergic receptors is critical for designing synthetic drugs that mimic natural effects.
    • Basic muscarinic receptor model shows needs for ester functionality and quaternary ammonium group separated by two carbons.
    • Different types of bonds exist in ACh, including ester and ionic bonds.

    SAR of Muscarinic Receptor Agonists

    • The ester portion of ACh binds through hydrogen bonds.
    • The quaternary ammonium portion binds through ionic bonds.
    • At least two methyls must be bonded to the quaternary nitrogen for potency.
    • A defined stereochemistry is important and following Ing's rule of five, involving the number of atoms separating important parts of the molecule.

    ACh Stereochemistry

    • ACh, while non-chiral, has different arrangements in 3D space caused by σ-bond rotations. Common isomers are synclinal and anticlinal. This affects interactions with receptors.

    ACh Mimetics - Muscarinic Agonists

    • Interactions of cholinergic agonists with muscarinic receptors trigger specific pharmacological responses related to tissue location (i.e., smooth muscle contraction, vasoconstriction, reduced heart rate).
    • ACh is not an ideal therapeutic agent because it is poorly absorbed and has non-specific effects.

    SAR of ACh

    • Three important functional regions include acyloxy, ethylene, and quaternary ammonium groups.

    SAR of ACh Quaternary Ammonium

    • Muscarinic activity requires a positively charged nitrogen. Replacing methyl groups significantly affects activity, with larger alkyl groups leading to inactivity and ethyl group replacement leading to antagonistic effects.

    SAR of Ethylene Bridge

    • Agonist activity decreases with increasing chain length in the ethylene bridge region and Ing's Rule of Five predicts maximum potency requires no more than five atoms between the terminal N and hydrogen bond. Larger analogues tend to have antagonistic effects.

    SAR of Ethylene Bridge

    • Replacing hydrogen atoms with alkyl groups impacts agonist activity, with larger groups decreasing activity.
    • Ing's Rule of Five pertains to the number of atoms between the nitrogen and terminal hydrogen, affecting muscarinic potency.
    • Larger alkyl groups can bind to the receptor but exhibit antagonistic activity instead.

    Stereochemistry and Acetyl-β-Methylcholine

    • Muscarinic receptors display stereoselectivity
    • S-enantiomer of methacholine is potent and equipotent to ACh, while the R-form is significantly less potent.
    • AChE hydrolyzes the S-enantiomer much slower than ACh, explaining the prolonged action.
    • The R-enantiomer does not get hydrolyzed by AChE and exhibits more antagonistic effects.

    SAR of Acyloxy Group

    • Aromatic choline esters usually act as antagonists
    • Stability to hydrolysis is important
    • Carbamic acid esters, e.g., Carbachol produce potent agonists of both muscarinic and nicotinic receptors.
    • Carbachol is less susceptible to hydrolysis by AChE and gastric acid, which increases its absorption.

    Ether and Ketone Analogues

    • Choline ethyl ether exhibits muscarinic activity but is not commonly used clinically.
    • Potent ketones can be designed by placing carbonyl groups in the same location as in ACh.
    • The duration of action differs compared to ACh.

    Practice Problem

    • Ing's Rule of Five does not apply to muscarine (natural agonist).

    Summary of ACh SAR

    • Essential components include a nitrogen atom (positive charge), appropriate alkyl group size at the nitrogen, an oxygen atom and a two-carbon unit between the oxygen and nitrogen.
    • Ing's rule should apply.

    Clinically Relevant Therapeutics:

    • Methacholine chloride, a racemic mixture, is clinically important.
    • A selective muscarinic agonist with the S-enantiomer being more potent.
    • Carbachol is a carbamate analogue of ACh with no receptor specificity and high resistance to hydrolysis.
    • Pilocarpine HCl is unique muscarinic agonist. Different routes of administration are available

    Clinically Relevant Therapeutics

    • Bethanechol Chloride (Urecholine) is a selective muscarinic agonist which can be administered orally.
    • Pilocarpine HCl has diverse uses and is a notable muscarinic agonist.

    Clinically Relevant Therapeutics

    • Cevimeline HCl is a non-classical muscarinic antagonist.

    AChE Inhibitors (AChEls)

    • AChEls (anticholinesterases) interfere with ACh breakdown in the synapse.
    • Increasing ACh concentration leads to increased muscarinic and nicotinic effects.

    AChE Inhibitors (AChEls)

    • AChEls (anticholinesterases) are indirect cholinomimetics, not acting on the receptor itself, but increasing the synaptic concentration of ACh.
    • Used in various disorders like myasthenia gravis, glaucoma, and some cognitive conditions with insecticides and chemical warfare agents as examples.

    AChE Mechanism of Hydrolysis

    • Hydrolysis of ACh occurs via sequential steps involving the catalytic serine residue of AChE.
    • Acetylated AChE is inactive and cannot bind any more ACh molecules.

    Reversible AChEls

    • Type I reversible AChEls are substrates for AChE, forming acetylated enzyme intermediates.
    • Aryl and alkyl carbamates are examples, and hydrolysis of the carbamate leads to regeneration of the active AChE (slower hydrolysis compared to acetylated enzyme).
    • Aryl carbamates show better affinity (stronger inhibition) compared to alkyl carbamates.

    Physostigmine

    • Physostigmine, a tertiary amine, is more lipophilic than other AChEls.
    • It readily crosses the blood-brain barrier (BBB).

    Other Aryl Carbamates

    • Neostigmine, also a carbamate ester and quaternary ammonium salt, is similar in structure and MOA to physostigmine.
    • Others, like pyridostigmine (Mestinon) and edrophonium chloride (Enlon) vary in structure but are valuable medicinal chemicals

    Irreversible AChEls

    • Phosphate esters are extremely stable to hydrolysis.
    • Irreversible AChE inhibitors like echothiophate iodide form very stable phosphate-enzyme complexes and are used topically but have a long-lasting effect.

    Acetylcholine Antagonists - Muscarinic Antagonists

    • Muscarinic antagonists have a high affinity for muscarinic receptors but do not have intrinsic activity.
    • They act as competitive antagonists, thus producing the opposite effect of ACh.
    • Clinically, they are used for GI and respiratory tract issues, overactive bladder and other issues

    Clinically Relevant Agents (SAR)

    • Atropine provided a structural model for designing muscarinic antagonists. The configuration of tropane rings places the amine and ester groups the same distance apart as in ACh.

    SAR of Muscarinic Antagonists

    • Substituents R1 and R2, crucial for potency, should be carbocyclic or heterocyclic rings.
    • The R3 substituent influences binding strength, with hydroxyl and hydroxymethyl groups being particularly effective in enhancing binding by participating in hydrogen bonding.
    • The X substituent may be an ester or an ether group.

    SAR of Muscarinic Antagonists

    • The nitrogen substituent is frequently a quaternary ammonium group but not always necessary.
    • The distance between the amine and the substituted carbon is not critical in potency.
    • Two methylene units are often present in highly potent compounds.

    Final Comments Muscarinic Antagonists

    • Antagonists compete with ACh at the receptor binding site.
    • Size and steric factors in the R1, and R2 substituents play a key role in the efficiency of competing with ACh.
    • Anticholinergic agents with quaternary ammonium groups are frequently administered orally or parenterally
    • The nature of the substituent on the tertiary nitrogen greatly affects absorption rates..

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    Description

    This quiz explores the structural requirements for compounds to exhibit muscarinic activity and the criteria of Ing's Rule of Five. Additionally, it covers various aspects of acetylcholinesterase (AChE) inhibitors and their effectiveness in pharmacology. Test your knowledge on how different structural modifications impact muscarinic potency and enzyme interaction.

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