PHID1502 Integrated Sequence 2 Med Chem Cholinergics Winter 2024-2025 PDF

Winter quarter 2024-2025 [email protected] 1 Integrated Sequence 2 – PHID1502 – Winter 2024-2025 Medicinal Chemistry of cholinergic agonists and antagonists Required reading: Foye’s, Sixth Edition – Chapter 12, pages 361 – 391, Fifth Edition Onlin...

Winter quarter 2024-2025 [email protected] 1 Integrated Sequence 2 – PHID1502 – Winter 2024-2025 Medicinal Chemistry of cholinergic agonists and antagonists Required reading: Foye’s, Sixth Edition – Chapter 12, pages 361 – 391, Fifth Edition Online – Chapter 9 Recommended: Katzung, Eleventh Edition - Chapter 7, pages 95 – 112, Chapter 8, pages 113-126. Oliver Grundmann, Ph.D. Adjunct Assistant Professor (MWU) Clinical Professor (UF) Phone: 352-246-4994 [email protected] Winter quarter 2024-2025 [email protected] 2 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  Winter quarter 2024-2025 [email protected] 3 The Parasympathetic Nervous System Rest and digest response – acetylcholine is the endogenous substance Winter quarter 2024-2025 [email protected] 4 Cholinergic nerve transmission Winter quarter 2024-2025 [email protected] 5 Cholinergic nerve transmission  Winter quarter 2024-2025 [email protected] 6 The muscarinic receptors All muscarinic cholinergic receptors are G-protein coupled receptors (GPCRs). GPCRs consist of: Transmembrane region with 7 loops, binding site for drugs is on the outside of the cell Coupled G-protein situated next to the receptor Separate enzyme unit that can be activated through diffusion of G-protein subunit to initiate secondary messenger cascade Winter quarter 2024-2025 [email protected] 7 The muscarinic receptors 1. Resting state of the GPCR 2. Activation of secondary messenger cascade following binding of an agonist to the receptor. 3. Diffusion of alpha- 1 subunit from receptor to effector (enzyme for 2 adrenergic receptors) and release of secondary messenger 4 4. Release of agonist from receptor leads to re- association of alpha-subunit with 3 receptor. Winter quarter 2024-2025 [email protected] 8 The nicotinic receptors All nicotinic cholinergic receptors are ion channels 5 transmembrane subunits Extracellular binding site for acetylcholine Ion channel specific to select ions (mostly for Na+, K+, and Ca2+) Genetic variations in subunits may account for certain disorders Winter quarter 2024-2025 [email protected] 9 The nicotinic receptors Subunits are further divided into subtypes with 17 isoforms identified to date Subunits determine the localization of the specific nicotinic receptor Muscle contraction ((α1)2β1γδ and (α1)2β1γε) Cognition and memory ((α7)5, (α4)2(β2)3) Pain perception ((α4)2(β2)3, (α3)2(β4)3) Brain reward ((α7)5, (α4)2(β2)3, (α3)2(β4)3) Winter quarter 2024-2025 [email protected] 10 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) Winter quarter 2024-2025 [email protected] 11 Parasympathomimetic drugs/cholinergic agonists - spectrum of action Pilocarpine Physostigmine Carbachol Echothiophate  Winter quarter 2024-2025 [email protected] 12 Natural agonists at cholinergic receptors Acetylcholine Muscarine Nicotine Muscarine Nicotine Natural product found in mushrooms Natural product found in tobacco (Amanita muscaria, fly agaric) (Nicotiana tabacum) Binds specifically to muscarinic Binds exclusively to nicotinic cholinergic receptors cholinergic receptors Various physiological effects on Various physiological effects on peripheral and central AChM receptors smooth muscles and on central AChN Winter quarter 2024-2025 [email protected] 13 Essential SAR for cholinergics Basic structure of cholinergics is 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 which can carry a positive charge Winter quarter 2024-2025 [email protected] 14 Cholinergic effects - mnemonic SLUDGE Salivation Lacrimation Urination Defecation Gastrointestinal upset Emesis If cholinergic receptors are stimulated, mostly observed with Direct muscarinic agonists (methacholine, bethanechol) Indirect muscarinic agonists (pyridostigmine, physostigmine, organophosphate agents)  Winter quarter 2024-2025 [email protected] 15 Essential SAR for cholinergics β α 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  Winter quarter 2024-2025 [email protected] 16 Essential SAR for cholinergics β α 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 is important – (S) isomer is equipotent with muscarine at muscarinic receptors while (R) isomer is 20 times less potent Substitution of methyl group in α position leads to decreased activity and may cause indirect agonist activity due to acetylcholine esterase enzyme inhibition  Winter quarter 2024-2025 [email protected] 17 Essential SAR for cholinergics β α 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  Winter quarter 2024-2025 [email protected] 18 Ester hydrolysis of acetylcholine Base hydrolysis: Acid hydrolysis: OH- H+ Completely Reversible until reversible, but ester bond is favors cleaved cleaved product H2O -OH- -H+ Winter quarter 2024-2025 [email protected] 19 Overview of muscarinic agents Direct muscarinic agonists Methacholine, carbachol & bethanechol Pilocarpine Cevimeline & arecoline Indirect muscarinic agonists Reversible inhibitors: physostigmine, neostigmine, pyridostigmine, carbaryl, edrophonium Alzheimer’s disease: tacrine, donepezil, rivastigmine & galantamine Irreversible inhibitors: echothiophate Insecticides & warfare agents: malathion, parathion, paraoxon & chlorpyrifos Direct muscarinic antagonists Atropine & scopolamine Tiotropium & ipratropium, oxybutynin & glycopyrrolate Trihexyphenidyl & tolterodine Solifenacin, darifenacin & propantheline Winter quarter 2024-2025 [email protected] 20 Direct muscarinic agonists Acetylcholine Methacholine Carbachol Bethanechol  Winter quarter 2024-2025 [email protected] 21 Methacholine & carbachol Methacholine: R1: quaternary nitrogen with methyl groups, confers strong interaction with receptor R2: β methyl substitution, reduces ester hydrolysis without reducing activity, selectivity for muscarinic receptors, stereoselectivity (S-isomer is equipotent to acetylcholine, R- isomer is 20 times less potent) R3: no change PK: Not orally available, duration of action 20-60 min., given via inhalation Indication: used for diagnosis of asthma, bronchial hyperreactivity Carbachol: R1: quaternary nitrogen with methyl groups, confers strong interaction with receptor R2: no substitution, no selectivity for muscarinic or nicotinic receptors R3: carbamate derivative, more resistant to metabolism via acid-, base-, or AChE hydrolysis PK: Not orally available, duration of action 1-2 h., given as ophthalmic solution Indication: limited to use in glaucoma and induction of miosis due to erratic absorption and receptor non-selectivity  Winter quarter 2024-2025 [email protected] 22 Bethanechol Bethanechol: R1: quaternary nitrogen with methyl groups, confers strong interaction with receptor R2: β methyl substitution, reduces ester hydrolysis without reducing activity, selectivity for muscarinic receptors, stereoselectivity (S-isomer is equipotent to acetylcholine, R- isomer is 20 times less potent) R3: carbamate derivative, more resistant to metabolism via acid-, base-, or AChE hydrolysis PK: Orally available, duration of action 2-4 h. Indication: used for postsurgical and postpartum urinary retention and abdominal distension Winter quarter 2024-2025 [email protected] 23 Direct muscarinic agonists - pilocarpine Acetylcholine Metabolic Pilocarpine Pilocarpic acid inactivation Inactive metabolites Isopilocarpine  Winter quarter 2024-2025 [email protected] 24 Pilocarpine Natural product (alkaloid) isolated from the leaves of the plant Pilocarpus jaborandi R1: tertiary nitrogen but mainly charged at physiological pH of 7.4 – does not cross the blood-brain barrier in significant amounts R2: extension of the bridge into imidazoline ring structure, does not follow the usual structure-activity relationship R3: lactone ring can be hydrolyzed, instability if formation of pilocarpic acid PK: available as ophthalmic solution or as tablets, half-life is variable with lower oral doses (5 mg) in the range of 1 h and higher doses (10 mg) around 2 h Indication: used for glaucoma and treatment of xerostomia and Sjögren’s syndrome Winter quarter 2024-2025 [email protected] 25 Direct muscarinic agonists Acetylcholine Cevimeline Arecoline  Winter quarter 2024-2025 [email protected] 26 Cevimeline & arecoline Cevimeline: R1: tertiary nitrogen in quinuclidine derivative, does not follow regular structure- activity principles Agonist at central M1 and peripheral M3 receptors in secretory glands PK: good bioavailability of 40-50%, peak plasma concentrations after 2 h, half-life of 3-5 h, elimination via oxidation, glucuronidation, and sulfation with the urine Indication: used for treatment of xerostomia Arecoline: Alkaloid present in Areca nut, commonly chewed in Asia for mild stimulant effects, but consumption has been linked to carcinogenic effects, M1 and M4 receptor agonist Does not follow structure-activity relationship, but contains certain features such as tertiary nitrogen, spacer, and ester PK: not known, but approximate duration of stimulant effects for 3-4 h. Indication: no clinical indication, potential benefits in Alzheimer’s disease, characteristic red mouth with continued chewing Winter quarter 2024-2025 [email protected] 27 Indirect cholinergic agonists – acetylcholine esterase inhibitors Acetylcholine is rapidly hydrolyzed after acting on postsynaptic receptors by the enzyme acetylcholine Acetylcholine esterase Present on the postsynaptic terminal Other isoform – pseudo- choline esterase – present in the bloodstream Choline Acetate Winter quarter 2024-2025 [email protected] 28 Reversible acetylcholine esterase inhibitors Reversible acetylcholine esterase inhibitors can also be referred to as indirect cholinergic agents since they Carbamate AChE increase the concentration of inhibitor acetylcholine in the synaptic cleft to act on postsynaptic receptors Carbamate forms more stable bond with AChE, takes longer to reconstitute enzyme Carbaminoyl – stable bond Winter quarter 2024-2025 [email protected] 29 Irreversible acetylcholine esterase inhibitors Organophosphate Irreversible acetylcholine AChE inhibitor esterase inhibitors are used as warfare agents since they inhibit the enzyme irreversibly and require resynthesis of the enzyme Exposure to irreversible AChE inhibitors is life-threatening “Aging” of the emergency bond prevents hydrolysis Only exception is echothiophate Winter quarter 2024-2025 [email protected] 30 Reversible acetylcholine esterase inhibitors – physostigmine & neostigmine Acetylcholine Basic structure of carbamate AChE inhibitors Physostigmine Neostigmine  Winter quarter 2024-2025 [email protected] 31 Physostigmine & neostigmine Physostigmine: Alkaloid isolated from the Calabar bean (Physostigma venenosum) R1: cyclic, ionizable tertiary nitrogen, confers strong interaction with receptor, allows for CNS penetration R2: does not resemble usual structure-activity requirement, but the aromatic ring interacts with the enzyme R3: carbamination of the enzyme with slow hydrolysis of bond PK: Mostly given intravenously, intramuscular, and ophthalmic, half-life of 1-2 hours, metabolism to inactive hydroxyl derivative (eseroline) after hydrolysis Indication: used for treatment of glaucoma, myasthenia gravis, and potentially Alzheimer’s disease (CNS penetration) Neostigmine: R1: quaternary nitrogen with methyl groups, confers strong interaction with receptor, no CNS penetration R2: does not resemble usual structure-activity relationship R3: carbamination of enzyme, but faster hydrolysis than for physostigmine PK: low oral bioavailability (5%), elimination half-life 50-90 min., given i.v. Indication: prophylaxis of postoperative abdominal distension and urinary retention, myasthenia gravis, and reversal of neuromuscular blockade Winter quarter 2024-2025 [email protected] 32 Reversible acetylcholine esterase inhibitors – pyridostigmine, carbaryl & edrophonium Acetylcholine Pyridostigmine Carbaryl Edrophonium  Winter quarter 2024-2025 [email protected] 33 Reversible acetylcholine esterase inhibitors – pyridostigmine, carbaryl & edrophonium Pyridostigmine: Similar to neostigmine, but less side effects PK: low oral bioavailability (10%), elimination half-life 1-2 h., metabolism to glucuronides Indication: used for treatment of myasthenia gravis, reversal of neuromuscular blocking agents, prophylaxis for nerve gas exposure Carbaryl: Not used in therapy, but commercially used as pesticide in house plants and for fleas and ticks in pets Edrophonium: Does not carbamylate AChE but still is a reversible inhibitor and cholinomimetic at skeletal muscles PK: given intravenously, half-life of 1-3 hours Indication: Edrophonium test for myasthenia gravis, reversal of non-depolarizing neuromuscular blocking agents (not effective in depolarizing neuromuscular blocking agents) Winter quarter 2024-2025 [email protected] 34 Reversible acetylcholine esterase inhibitors – CNS active compounds Tacrine Donepezil Rivastigmine Galantamine  Winter quarter 2024-2025 [email protected] 35 Reversible acetylcholine esterase inhibitors – CNS active compounds All CNS active reversible AChE inhibitors are being to slow the progression of Alzheimer’s disease since acetylcholine dysfunction and deficiency has been observed in various areas of the brain Tacrine: Shows improvement in 20% of Alzheimer patients, but hepatotoxic effects PK: half-life of 1.5 to 4 hours with hydroxylation and glucuronidation Donepezil: Greater affinity for brain AChE over peripheral AChE, no hepatotoxicity PK: half-life of 70-104 hours, metabolism via CYP enzymes Rivastigmine: Structurally similar to other carbamate AChE inhibitors PK: half-life of 1-2 hours, but AChE inhibition lasts for 10 hours due to slow hydrolysis Galantamine: Alkaloid isolated from daffodils & snowflakes, both reversible AChE inhibitor and nicotine agonist PK: half-life of 5-6 hours Winter quarter 2024-2025 [email protected] 36 Irreversible acetylcholine esterase inhibitor – echothiophate Acetylcholine General structure of organophosphate AChE inhibitors Echothiophate  Winter quarter 2024-2025 [email protected] 37 Irreversible acetylcholine esterase inhibitors – Echothiophate Echothiophate is the only irreversible acetylcholine esterase inhibitor used in therapy, a phosphorothioate derivative PK: long-lasting inhibition of AChE for up to 4 weeks, only available as ophthalmic solution Indication: treatment-resistant glaucoma (reduction in intraocular pressure) and strabismus Winter quarter 2024-2025 [email protected] 38 Irreversible acetylcholine esterase inhibitor – organophosphate insecticides Acetylcholine General structure of organophosphate AChE inhibitors Parathion Malathion metabolized to Chlorpyrifos Paraoxon  Winter quarter 2024-2025 [email protected] 39 Irreversible acetylcholine esterase inhibitors – organophosphate insecticides No therapeutic applications for organophosphate insecticides All based on organophosphate structure, irreversible phosphorylation of AChE Potential for aging of the bond under release of an alcohol Insecticides show higher affinity for insect choline esterase over human AChE Severe poison cases have to be treated immediately: Preserve airway access and maintain breathing Administer anticholinergic (atropine) potentially as i.v. drip Administer antidote pralidoxime to reverse binding and prevent aging of phosphate bond with enzyme Give benzodiazepines if seizures occur Supportive care may last for weeks or months Pralidoxime Winter quarter 2024-2025 [email protected] 40 Cholinergic antagonists (parasympatholytics) Categorized into muscarinic and nicotinic antagonists Muscarinic antagonists Eye: cause mydriasis, used for eye diagnosis (as eye drops) Bladder: reduction in contraction (p.o.) Lungs: widening of lungs, treatment of asthma and COPD (mostly inhaled) Brain stem: prevention of nausea and vomiting (via patch) GI and genitourinary: relaxation of smooth muscles Nicotinic antagonists: Neuromuscular junction: blocking of muscle contractions, used during surgery Winter quarter 2024-2025 [email protected] 41 Direct muscarinic antagonists - SAR Acetylcholine R1 and R2: substitutions of aromatic ring systems or heterocylic rings possess highest antagonist activity, limited to 6- membered rings (naphthalene is too large to allow for binding to receptor site) R3: can be a hydrogen, hydroxyl, methoxy, or alike small group, may enhance potency of antagonist through additional binding with receptor Winter quarter 2024-2025 [email protected] 42 Direct muscarinic antagonists - SAR Acetylcholine X: most potent is ester, but not necessary since also metabolized via esterases fast, can be an ether, or completely absent Alkyl linker: distance between ring-substituted carbon and nitrogen may not be critical if conformation of the molecule allows for orientation within receptor site, but usually between 2-4 carbon atoms long, most potent with 2 carbon atoms Winter quarter 2024-2025 [email protected] 43 Direct muscarinic antagonists - SAR Acetylcholine Nitrogen substitution: most potent if quaternary nitrogen, but if tertiary and ionizable (basic) at physiological pH then also possible, substitutions R4, R5, and R6 can be small alkyl substituents such as methyl, ethyl, propyl, or isopropyl  Winter quarter 2024-2025 [email protected] 44 Direct muscarinic antagonists - atropine Natural product (alkaloid) isolated from various Solanaceae species, deadly nightshade (Atropa belladonna), jimsonweed (Datura stramonium) R1 and R2: aromatic ring and hydrogen atom, high affinity for receptor, asymmetric center leads to different potencies isomers are called hyoscyamine, racemate is atropine R3: methylenehydroxyl group, enhances receptor interaction * X: ester, high affinity for receptor but also rapid hydrolysis by esterases and non-enzymatic hydrolysis Spacer: tropane bicyclic ring system, archetype of muscarinic antagonists in nature Nitrogen: tertiary nitrogen, basic and ionized at physiological pH, limited CNS penetration PK: 50% bioavailability, distribution throughout body, protein-binding of 44%, half-life of 4 h (adults) to 6.5 h (children), N-demethyl and N-oxides are less active and inactive metabolites, can be given p.o., i.m., i.v., and rectal Indication: treatment of bradycardia (not common), preoperative to reduce secretion, organophosphate poisoning, contraindicated in glaucoma  Winter quarter 2024-2025 [email protected] 45 Direct muscarinic antagonists - scopolamine Natural product (alkaloid) isolated from various Solanaceae species, henbane (Hyoscyamus niger), jimsonweed (Datura stramonium) R1 and R2: aromatic ring and hydrogen atom, high affinity for receptor, only occurring as (-)-hyoscine R3: methylenehydroxyl group, enhances receptor interaction X: ester, high affinity for receptor but also rapid hydrolysis by * esterases and non-enzymatic hydrolysis Spacer: tropane bicyclic ring system, only difference to atropine is ether bridge to form a tricylic ring system Nitrogen: tertiary nitrogen, basic and ionized at physiological pH, increased CNS penetration than atropine because less ionized PK: 10-50% bioavailability depending on route, higher CNS penetration than atropine, half-life of 8 h, N-demethyl and N-oxides are less active and inactive metabolites, can be given p.o., i.m., i.v., s.c., transdermal, and rectal Indication: patch for treatment of motion sickness, causes CNS depression in contrast to atropine which causes CNS stimulation  Winter quarter 2024-2025 [email protected] 46 Direct muscarinic antagonists – tiotropium & ipratropium Tiotropium Ipratropium * R1 and R2: thiazol bioisosters of aromatic ring R3: hydroxyl group for increased receptor R1 and R2, R3, X, Spacer: same as affinity atropine X, Spacer: same as atropine, tricyclic ring Nitrogen: quaternary nitrogen, system permanent charge prevents CNS Nitrogen: quaternary nitrogen, permanent penetration charge prevents CNS penetration PK: low bioavailability, half-life of 2 h, PK: 19.5% bioavailability after inhalation, only given via inhalation half-life of 5-6 days, only given via inhalation Indication: asthma and COPD Indication: asthma and COPD  Winter quarter 2024-2025 [email protected] 47 Direct muscarinic antagonists – oxybutynin & glycopyrrolate * Glycopyrrolate Oxybutynin R1 and R2: aromatic and saturated ring R1 and R2: aromatic and saturated ring R3: hydroxyl group for receptor interaction R3: hydroxyl group for receptor interaction X: ester, subject to hydrolysis X: ester, subject to hydrolysis Spacer: triple bond confers rigidity Spacer: pyrrolidine ring Nitrogen: tertiary nitrogen, basic with Nitrogen: quaternary nitrogen, permanent limited CNS effects charge prevents CNS penetration PK: high first-pass metabolism, half-life of PK: 5% oral bioavailability, half-life of 0.6- 13 h, given as patch, N-deethyl 1.2 h, mostly given i.v. metabolite accumulates and causes side effects, preference for M3 receptors Indication: preoperative to decrease gland secretion, reversal of neuromuscular block Indication: urinary incontinence, spasms  Winter quarter 2024-2025 [email protected] 48 Direct muscarinic antagonists – trihexyphenidyl & tolterodine * Tolterodine Trihexyphenidyl R1 and R2: aromatic rings with partial R1 and R2: aromatic and saturated ring substitution for receptor interaction R3: hydroxyl group for receptor interaction R3: absent, reduced receptor affinity X: not present, not required for receptor X: absent, not required for receptor Spacer: simple alkyl linker Spacer: simple alkyl linker Nitrogen: tertiary nitrogen, good CNS Nitrogen: basic tertiary nitrogen with 2 penetration, M1 receptor preference isopropyl substitutions, limited CNS entry, M2 and M3 receptor preference, less side PK: high bioavailability, onset of action effects after 1 h, half-life of 3-4 h, duration of action 6-12 h PK: 77% oral bioavailability, half-life of 2-4 h, high protein binding (96%) Indication: Parkinson’s disease Indication: urinary incontinence  Winter quarter 2024-2025 [email protected] 49 Direct muscarinic antagonists – solifenacin, darifenacin & propantheline Darifenacin Solifenacin Indication: for urinary incontinence and bladder spasms by acting on M3 receptors (solifenacin and darifenacin), GI spasms and irritable bowel syndrome (propantheline) PK: variable bioavailability (90% solifenacin, Propantheline 15-20% darifenacin), half-life (45-68 h solifenacin, 13-19 h darifenacin), high protein binding (over 95%) Winter quarter 2024-2025 [email protected] 50 Overview of nicotinic agents Direct nicotinic agonists Varenicline & epibatidine Direct nicotinic antagonists Depolarizing neuromuscular blocking agents: decamethonium & succinylcholine Non-depolarizing neuromuscular blocking agents: Pancuronium, vecuronium, mivacurium & doxacurium Winter quarter 2024-2025 [email protected] 51 Nicotinic agonists - varenicline Synthetic derivative of natural product cytisine Secondary amine allows for transport into the CNS with predominantly central effects Partial agonist at (α4)2(β2)3 and full agonist at (α7)5 receptors Used in the treatment of smoking addiction, reduces craving and associated withdrawal effects, currently investigated for use in treatment of drug addiction PK: 100% oral bioavailability, half-life of 1 day, low metabolism rate to N- glucuronide Side effects: initially suicidal thoughts, headache, nausea, vomiting, insomnia, alteration in taste Winter quarter 2024-2025 [email protected] 52 Epibatidine Natural alkaloid isolated from the skin glands of the Ecuadorian frog Epipedobates tricolor High affinity and agonist activity at nicotinic subtypes β2 > α4 > α7 Potent analgetic (100-200 times potency of morphine) due to preference for (α4)2(β2)3 receptors Causes paralysis in high concentration at muscarinic receptors Derivatives are being researched for medical applications Winter quarter 2024-2025 [email protected] 53 Neuromuscular blocking agents Categorized into depolarizing and non-depolarizing agents High affinity for (α1)2β1γε nicotinic receptors on neuromuscular junction Used in general anesthesia for immobilization and prevention of muscle movement (mostly non-depolarizing agents) Used in endotracheal intubation (depolarizing agents) Also for controlled ventilation Winter quarter 2024-2025 [email protected] 54 Neuromuscular blocking agents Depolarizing agents Succinylcholine Decamethonium Non-depolarizing agents Tetrahydrosioquinoline derivatives Atracurium, mivacurium, doxacurium, tubocurarine Aminosteroid derivatives Pancuronium, vecuronium, rocuronium, rapacuronium, pipecuronium Winter quarter 2024-2025 [email protected] 55 Depolarizing neuromuscular blocking agents Depolarizing agents cause a permanent depolarization of the muscle fiber membrane potential and prevents repolarization Fast onset of action and short duration of action is important Winter quarter 2024-2025 [email protected] 56 Depolarizing neuromuscular blocking agents - decamethonium First neuromuscular blocking agent, not used clinically because of side effects High flexibility for interaction with receptor with 10-12 carbon atom chain, similar to acetylcholine with two quaternary nitrogen atoms Winter quarter 2024-2025 [email protected] 57 Depolarizing agents – receptor interaction Acetylcholine Decamethonium Two acetylcholine molecules necessary to active neuromuscular endplate for muscle contraction Quaternary nitrogens interact with receptor and carbonyl interaction to open ion channel One molecule of decamethonium or succinylcholine necessary to interact with receptor Quaternary nitrogens interact with receptor to cause depolarization Winter quarter 2024-2025 [email protected] 58 Depolarizing neuromuscular blocking agents - succinylcholine Two molecules of acetylcholine connected via a succinic acid, flexible molecule, 10 carbon atom distance between quaternary nitrogen atoms Also referred to as suxamethonium chloride Quaternary nitrogen atoms prevent CNS effects Rapid metabolism via ester hydrolysis, short half-life of 5- 10 min., rapid onset of action under 1 min. following intravenous injection  Winter quarter 2024-2025 [email protected] 59 Non-depolarizing neuromuscular blocking agents First non-depolarizing agent is a natural alkaloid, tubocurarine, that was used for hunting as an arrow poison Causes muscle relaxation and prevents contraction, more potent at neuromuscular endplate but will also act on other nicotinic receptors, causing respiratory paralysis in high concentrations Not bioavailable after oral administration, thus cooking of the meat of hunted animals is safe for consumption Winter quarter 2024-2025 [email protected] 60 Non-depolarizing neuromuscular blocking agents – receptor interaction Interaction of vecuronium with nicotinic acetylcholine receptors on the neuromuscular endplate Non-depolarizing blocking agents are competitive antagonists at the nicotinic neuromuscular junction Prevents binding and activation of the ion channel by acetylcholine Can be reversed with administration of acetylcholine or increased acetylcholine concentrations (anticholinergics) Mainly classification into short, intermediate, and long-acting agents Winter quarter 2024-2025 [email protected] 61 Non-depolarizing agents - tubocurarine Natural alkaloid isolated from the plant Chondrodendron tomentosum (Menispermaceae), from which curare has been extracted as an arrow poison Two benzylisoquinoline molecules with a 10 carbon distance between the quaternary nitrogen atoms Not used in clinical due to side effects (histamine release, ganglionic blockade of nicotinic receptors, less control of pharmacokinetics) Long-acting non-depolarizing agent Winter quarter 2024-2025 [email protected] 62 Non-depolarizing agents - atracurium Atracurium Laudanosine First non-depolarizing agent in clinical use Two tetrahydroisoquinoline derivatives separated by ester bridge General SAR: number of methoxy groups increase antagonist potency at nicotinic receptors Given intravenously, half-life of 20 min., intermediate acting with 40 min. duration Metabolized by plasma esterases, not in the liver, generation of toxic metabolite laudanosine (hypotension, CNS stimulation, seizures) through non-enzymatic Hofmann elimination Winter quarter 2024-2025 [email protected] 63 Non-depolarizing agents – mivacurium & doxacurium Doxacurium Mivacurium Mivacurium: more methoxy groups but less flexible ester bridge, mixture of isomers Half-life of 2 min., short acting (15 min.), no toxic metabolites, less side effects Doxacurium: more methoxy groups and higher potency, flexible connecting ester chain Half-life of 90-120 min., long-acting (70-100 min.), no toxic metabolites, less side effects, high potency requires lower dose  Winter quarter 2024-2025 [email protected] 64 Non-depolarizing agents – pancuronium D A Pancuronium: aminosteroid derivative Orientation of ring system important for receptor interactions: A ring has trans-geometry with quaternary nitrogen group pointing upwards and acetoxy group downwards: M2 receptor antagonist activity (side effect tachycardia) D ring has cis-geometry with quaternary nitrogen group and acetoxy group pointing upwards: nicotinic receptor antagonist activity Short onset of action (3 min.), used in euthanasia and executions Half-life 2 h, long-acting agent (2-3 h), causes histamine release (side effects), metabolism via hydroxylation to inactive metabolites  Winter quarter 2024-2025 [email protected] 65 Non-depolarizing agents – vecuronium D A Vecuronium: aminosteroid derivative Orientation of ring system important for receptor interactions: A ring same as for pancuronium, but tertiary nitrogen group which leads to 100 times less muscarinic antagonist activity than pancuronium D ring same as for pancuronium Short onset of action (3 min.) Half-life 50-80 min., intermediate-acting agent (40 min.), metabolism to active hydroxyl metabolites, risk of accumulation with prolonged muscle paralysis after prolonged exposure Winter quarter 2024-2025 [email protected] 66 Non-depolarizing agents - classification Drug Potency Onset Half-life Duration Short-acting Mivacurium 4 2-4 min. 1.8-2 min. 12-18 min. Rapacuronium 0.4 ? ? 10-20 min. Intermediate-acting Atracurium 1.5 2-4 min. 16-20 min. 30-40 min. Vecuronium 6 2-4 min. 65-80 min. 30-40 min. Rocuronium 0.8 1-2 min. 84-131 min. 30-40 min. Long-acting Tubocurarine 1 4-6 min. 170 min. 80-120 min. Doxacurium 6 4-6 min. 72-96 min. 90-120 min. Pancuronium 6 4-6 min. 90-140 min. 120-180 min. Pipecuronium 6 2-4 min. 137-161 min. 80-100 min. Potency relative to tubocurarine