Cholinergic Drugs and Muscarinic Receptors Quiz

Integrated Sequence 2 – PHID1502 – Winter 2024-2025

• Course Topic: Medicinal Chemistry of cholinergic agonists and antagonists
• Required Reading: Foye's, Sixth Edition – Chapter 12, pages 361–391; Fifth Edition Online – Chapter 9
• Recommended Reading: Katzung, Eleventh Edition – Chapter 7, pages 95–112; Chapter 8, pages 113–126.
• Instructor: Oliver Grundmann, Ph.D.
• Instructor Contact Information: Phone: 352-246-4994; Email: [email protected]

Outline

• Review of the mechanism of action of direct and indirect-acting cholinergic agonists and antagonists
• Structure-activity relationship of muscarinic agonists and antagonists
• Pharmacokinetic properties and routes of metabolism of muscarinic agents
• Structure-activity relationship of nicotinic agonists and antagonists
• Pharmacokinetic properties and routes of metabolism of nicotinic agents

The Parasympathetic Nervous System

• Endogenous Substance: Acetylcholine
• System Function: Rest and digest response
• Includes diagrams of pathways and target organs

Cholinergic Nerve Transmission

• Neurotransmitter: Acetylcholine (ACh)
• Synthesis: Acetyl-CoA + choline → ACh
• Enzyme: Choline acetyltransferase (ChAT)
• Storage: Vesicles
• Release: Calcium influx triggers exocytosis
• Receptor Interaction: Binding to receptors
• Inactivation: Acetylcholinesterase (AChE) breaks down ACh into acetate and choline
• Diagrams showing the process

The Muscarinic Receptors

• Type: G-protein coupled receptors (GPCRs)
• Structure: Transmembrane region with 7 loops, binding site for drugs on the outside of the cell
• GPCR components:
• Transmembrane region with 7 loops
• Binding site for drugs on the outside of the cell
• Coupled G-protein
• Separate enzyme unit
• Functions of G-protein subunit diffusion initiate secondary messenger cascades
• Diagrams showing the functions of GPCRs

The Nicotinic Receptors

• Type: Ion channels
• Structure: 5 transmembrane subunits
• Acetylcholine binding site: Extracellular site
• Ion channel selectivity: For Na+, K+, and Ca2+
• Subunit variations: May account for genetic disorders
• Diagrams showing the location of acetylcholine binding site and structure of subunits

Subunit Types

• Muscle contraction (α₁)2β₁γδ and (α₁)2β₁γε
• Cognition and memory (α7)5, (α4)2(β2)3
• Pain perception ((a4)2(β2)3, (α3)2(β4)3)
• Brain reward ((α7)5, (α4)2(β2)3, (α3)2(β4)3)
• Subunits determine localization of specific receptor

Potential Drug Targets for Cholinergic Nerve Transmission

• Synthesis of acetylcholine (hemicholinum)
• Storage of acetylcholine in intracellular vesicles (vesamicol)
• Release of acetylcholine (botulinum toxin)
• Action on postsynaptic receptors (direct muscarinic and nicotinic agonists & antagonists)
• Degradation of acetylcholine (acetylcholine esterase inhibitors)
• Diagrams showing different stages of nerve transmission

Parasympathomimetic drugs/cholinergic agonists

• Pilocarpine, Physostigmine, and Echothiophate
• Types of cholinergic receptor
• Stimulation of the various receptors
• Indications and modes of administration

Natural Agonists at Cholinergic Receptors

• Muscarine (mushrooms) and Nicotine (tobacco)
• Effects on cholinergic receptors and organs

Essential SAR for Cholinergics

• Basic structure of cholinergics (acetylcholine)
• Acetyl is hydrophilic and provides necessary oxygen for receptor interaction . Choline is essential for receptor interaction and contains spacer (ethylene bridge) as well as basic nitrogen that can carry a positive charge

Cholinergic Effects - Mnemonic

• SLUDGE: Salivation, Lacrimation, Urination, Defecation, Gastrointestinal upset, and Emesis
• Direct and indirect muscarinic agonist effects

Essential SAR for Cholinergics (if R₁ = )

• Highest activity seen with nitrogen atom, requires possibility of carrying positive charge
• Methyl groups are required for agonist activity, larger substituents (ethyl groups) will confer antagonist activity
• Replacing methyl groups with hydrogen will lead to successively lower agonist activity

Essential SAR for Cholinergics (if R₂ = )

• Larger spacers than ethylene lead to reduced activity and may lead to antagonist effects (rule of five: not more than 5 atoms between the quaternary nitrogen and the terminal oxygen)
• Substitution of methyl group in β position leads to increased selectivity for muscarinic receptors, stereoselectivity (S) is equipotent with muscarine at muscarinic receptors while (R) isomer is 20 times less potent
• Substitution of methyl group in position a leads to decreased activity

Essential SAR for Cholinergics (if R₃ = )

• Potency and activity decrease with larger alkyl groups such as propionyl or butyl esters, aromatic substitution will lead to antagonist activity
• Ester is prone to rapid hydrolysis by ubiquitously present esterases
• Modification of ester does not affect selectivity for muscarinic vs. nicotinic receptors
• Replacement of methyl group with amine group (carbamate) results in more stable ester and longer duration of action
• Ether derivatives also provide for higher stability but are not used in the clinical setting

Ester Hydrolysis of Acetylcholine

• Acid hydrolysis: reversible until ester bond is cleaved
• Base hydrolysis: completely reversible, but favors cleaved product
• Diagrams of the reaction steps

Overview of Muscarinic Agents

• Direct muscarinic agonists
• Indirect muscarinic agonists
• Direct muscarinic antagonists

Direct Muscarinic Agonists

• Methacholine, carbachol, bethanechol
• Pilocarpine
• Cevimeline & arecoline

Direct Muscarinic Antagonists

• Atropine, scopolamine
• Tiotropium & ipratropium
• Oxybutynin & glycopyrrolate
• Trihexyphenidyl & tolterodine
• Solifenacin, darifenacin & propantheline

Overview of Nicotinic Agents

• Direct nicotinic agonists
• Direct nicotinic antagonists
• Depolarizing neuromuscular blocking agents
• Non-depolarizing neuromuscular blocking agents

Nicotinic Agonists

• Varenicline & epibatidine

Epibatidine

• Natural alkaloid isolated from skin glands of the Ecuadorian frog
• High affinity and agonist activity at nicotinic subtypes with predominantly central effects

Neuromuscular Blocking Agents

• Categorized into depolarizing and non-depolarizing agents
• High affinity for (α₁)2β₁γε nicotinic receptors on neuromuscular junction
• Used in general anesthesia, immobilization and prevention of muscle movement
• Used in endotracheal intubation

Depolarizing Agents

• Succinylcholine
• Decamethonium
• Mechanism of action, and their clinical implications

Depolarizing neuromuscular blocking agents

• Decamethonium
• Succinylcholine
• Mechanism of action, and clinical implications

Non-depolarizing agents

• Tubocurarine
• Atracurium
• Mivacurium
• Doxacurium
• Pancuronium
• Mechanism of action, duration of action and clinical implications

Non-depolarizing Agents - Classification

• Table listing drugs, potency, onset, half-life, and duration

Reversible Acetylcholine Esterase Inhibitors

• Physostigmine, neostigmine
• Pyridostigmine, carbaryl, and edrophonium
• Mechanism of action and their clinical efficacy

Irreversible Acetylcholine Esterase Inhibitors

• Echothiophate, Organophosphates, Insecticides
• Clinical relevance, mechanisms, specific examples
• Including indications and pharmacokinetics

Cholinergic Antagonists (Parasympatholytics)

• Categorized into muscarinic and nicotinic antagonists
• Muscarinic antagonists and their effects on specific organs and systems
• Nicotinic antagonists and their effects on neuromuscular junctions