Cholinergic Drugs & Related Agents PDF

Cholinergic drugs and related agents Prepared by Abdallah E. Abdallah, PhD Associate Prof. of Pharmaceutical Chemistry Cholinergic agents Molecules that produce effects similar to those of acetylcholine. These effects can be achieved either...

Cholinergic drugs and related agents Prepared by Abdallah E. Abdallah, PhD Associate Prof. of Pharmaceutical Chemistry Cholinergic agents Molecules that produce effects similar to those of acetylcholine. These effects can be achieved either by direct stimulation of the cholinergic receptors (cholinomimetics or parasympathomimetics), or by inhibition the acetylcholine esterase (acetylcholine esterase inhibitors).  O Choline acetylase Acetyl HO N + Acetyl Co-A O N+ Choline choline Acetylcholine Muscarinic effect Nicotinic effect at the postganglionic nerve endings at autonomic ganglia at neuromuscular junction N N HO N N N O O Muscarine Nicotine O Pilocarpine  H. bond O O N N O CH3 O Ionic bond Van der Waals Ionic bond H. bond interactions O O H H N N O O Muscarinic receptor Nocotinic receptor Representative illustration for the two different binding modes of acetycholine to muscarinic and nicotinic reseptors.Notice the same conformation of the acetylcholine. Acetylcholine therapeutic value Acetylcholine itself has no therapeutic value because of its rapid hydrolysis. However, it can be used as a short acting miotic to produce miosis after cataract surgery. O O Acetylcholine esterase N+ N HO + OH O Choline acetic acid Acetylcholine analogs The main purpose of development of acetylcholine analogs is prolongation its duration of action. Examples: methacholine, carbachol, and bethanchol  Its steric effect delays the Methacholine hydrolysis of methacholine by acetycholine esterase, So, prolong the duration to some extent O CH3 N+ Cl O Methacholine Very short acting miotic used for emergency treatment of angle-closure glaucoma Chemical synthesis of methacholine H OH N OH HOCl CH3COOH O Cl N N O CH3Cl Cl O N O Methacholine (2-Acetoxypropyl)-trimethylammonium chloride Assay of methacholine 1- Volhard's method: a method of indirect titration in which a known excess of silver nitrate solution is added to precipitate chloride ion, the residual silver is back titrated with standard solution of ammonium thiocyanate + - using iron (III) ammonium Ag + sulfate asAgSCN SCN indicator. +3 - +2 Fe + SCN FeSCN red color Assay of methacholine 2- Saponification method which depends on hydrolysis of methacholine by known excess of NaOH solution, and the residual NaOH is back titrated with standard solution of HCl.  Carbachol Isosteric replacement of CH3 by NH2 Treatment of glaucoma. gave crbamate greoup that resists As a replacement of hydrolysis by esterase, So it has long pilocarpine. duration of action To relieve urine retention. O N+ Cl H2N O Carbachol  O Cl Cl O O NH3 O O HOCl HO Cl Cl Cl Cl NH2 N Chemical synthesis of carbachol O N+ Cl H2N O Carbachol Assay : Volhard's method Bethanechol Increases resistance to Resistance to O CH3 acetylcholineesterase acetylcholinesterase H2N O N+ Cl Increases the lipophilicity Bethanechol 2-Caramoyloxypropyl-trimethyl-ammonium chloride Prolonged effect. Used for stimulation of GIT and urinary tract in case of postoperative atony. Used to relieve urine retention and in paralytic ileus. In glaucoma. SAR 1- Quaternary ammonium is essential for activity. It forms Ester group is not essential essential ionic bond. for activity, O 2- Replacement of one methyl N+ group by larger alkyl one -inverted ester is 15 times O as potent as acetylcholine decreases the activity. Acetylcholine 3- Replacement of two methyl O N+ Cl groups by larger alkyl groups O leads to loss of activity. - 4- Hydroxypentyltrimethylammonium Ethylene bridge is the proper distance chloride is about 1500 times as between the ammonium and ester. potent as acetylcholine - Elongation the distance between OH N+ both groups lead to decrease in Cl- activity. SAR O N+ O Acetylcholine O O N+  N+ O  O Strong muscarinic effect O weak nicotinic effect N+ Strong nicotinc effect O weak muscarinic effect Pivaloylcholine 10 times as potent as acetylcholine in muscarinic effects 10 times less active in nicotinic effects Acetylcholinesterase inhibitors Inhibition of acetylcholine esterase may be reversible or irreversible. Reversible inhibitors compete acetylcholine at the active site of the enzyme. Irreversible inhibitors are non competitive. Reversible competitive anticholinesterase Short acting. Stimulate peristalsis in post operative atony. Myasthenia gravis treatment. N O N Antidote of gallamine and O Br tabocurarine. Neostigmine bromide 3-((Dimethylcarbamoyl)oxy)- N,N,N-trimethylbenzenaminium bromide Glaucoma.  Chemical synthesis of neostigmine O HO OH H N HO N Cl Cl Cl O N O   pressure Resorcinol H N N O N CH3Br O N O N Br O Neostigmine bromide Assay of neostigmine Volhard's method. Non aqueous titration with perchloric acid Hydrolysis by NaOH, collecting the liberated dimethylamine in boric acid solution and titration with standard solution of sulfuric acid using methyl red as indicator. N O N H NaO N N + CO2 + O Br Br Neostigmine bromide H H 2 H H2SO4 N SO4 N + 2 Pyridostigmine bromide Short acting competitive reversible anticholinesterase. Used orally for Myasthenia O N gravis. O N Antagonist for neuromuscular Br blocker. Pyridostigmine bromide 3-((Dimethylcarbamoyl)oxy)-1-methylpyridin-1-ium bromide  Chemical synthesis of pyridostigmine OH O N O N Cl N CH3Br + O O N O N N Br  Distigmine Competitive reversible choline esterase inhibitor with longer duration of action compared to neostigmine and pyridostigmine. Oral and injection (prescription only). Used for treatment of underactive detrusor and voiding dysfunction. Br N O O N N O O N Br Rivastigmine N O N O 3-(1-(Dimethylamino)ethyl)phenyl dimethylcarbamate Pseudo irreversible non-competitive carbamate inhibitor of acetyl choline esterase. T1/2 is about 2 h. The inhibitory properties of the drug lasts for about 10 h. Symptomatic treatment of Alzheimer.  O Acetyl choline N+ O O N N O rivastigmine rivastigmine Acetyl choline  Irreversible choline esterase inhibitors They act on serine amino acid of acetylcholine, forming covalent bond (phosphate or thiophosphate ester). Example: organic phosphates such as Malathion, parathion, and sarin (a nerve gas). Organophosphorous compounds are neurotoxic used as chemical weapon and insecticide O O O NO2 S O S O O P P S P O O O O F O Parathion Sarin Malathion  Toxicity of organophosphates O O P Y O O O O P O O P O OH covalent bond O O serine + Y acetylcholine esterase phosphorylate acetylcholine esterase aged acetylcholine esterase inactive enzyme  Antidote for organophosphate toxicity O O O P O O P O cholinesterase reactivator O O such as Pralidoxime inactive aged acetylcholine esterase chloride. acetylcholine esterase The antidote should be N N OH used as soon as possible. Cl Atropine but the Pralidoxime chloride oxygenation should be optimized before its use to OH O O minimize the possibility of + N P N O O arrythmia. reactivated enzyme Cl Anticholinergic agents Anticholinergic drugs antimuscarinic antinicotinic ganglionic blocker neuromuscular blocker  Antimuscarinics (parasympatholytics) Competitive reversible antagonists of acetylcholine at muscarinic receptors. The earliest known anticholinergic agents are extracts of Atropa Belladonna, Hyoscyamus Niger, and Datura Stramonium. Atropine is the first anticholinergic agent to be identified. Hyoscine (scopolamine) has similar biological effects of atropine  HO O N O O N O O OH Atropine Scopolamine  SAR of antimuscarinic drugs Quaternary or at least tertiary nitrogen protonated in blood. It should carry small alkyl X may be ester groups or ether For maximal antagonist activity R1 and R2 should be two ring R3 should be OH, CH2OH R1 X N+ system (carbocyclic or n or CONH2. to form R2 heterocyclic), at least one of R3 hydrogen bond to the them is aromatic. They should receptor be bulky and hydrophobic n = 2 to 4 Essential structural features showing similarity to acetylcholine structure Antimuscarinic drugs classification According to chemical structure 1- Atropine and its analogs 2- Quaternary ammonium compounds 3- Miscellaneous  O N N H O reduction H NH2 Atropine O + + chemical Succinic dialdehyde Tropinone O OH synthesis O HO OH Tropic acid H N N H2SO4 O O O O OH OH 2 SO4 Atropine Atropine sulfate tropyl ester of tropic acid racemic form of (-)- hyoscyamine Assay of atropine Non aqueous titration with 0.1M perchloric acid Homatropine Br H Atropine analog N Mandelic acid ester. O Synthetic alkaloid. O OH Homatropine bromide  Homatropine synthesis O H OH OH OH H H2O NaHSO 3 NaCN SO3Na CN COOH Br N H N N OH O HBr O Tropinol O O OH OH Homatropine bromide Homatropine Assay of homatropine 1- Titration with ceric (IV) ammonium nitrate. 2- Saponification with NaOH. Br H N 2 O O OH 1 Homatropine bromide Uses Homatropine is used mainly as mydriatic It is better than atropine as mydriatic in the sense that 1- it is relatively rapid acting 2- less duration of action 3- more easily controlled by physostigmine. Homatropine is used orally as antispasmodic. Hyoscyamine Hyoscyamine is the levo form of the racemic mixture known as atropine. The dextro form does not exist naturally but has been synthesized. Scopolamine (Hyoscine) Natural alkaloid. N It is the levo component of the O racemic mixture that is known as O atroscine. O OH The alkaloid is racemized readily in the presence of dilute alkali. Scopolamine (Hyoscine) Ipratropium bromide It is a quaternary ammonium derivative of atropine. N Br The salt is stable in neutral and acidic O solutions but rapidly hydrolyzed in alkaline O OH solutions. Ipratropium bromide Used in acute asthmatic attack but not alone because its onset of action is from 5- 15 min. Tiotropium bromide Br It is indicated in the treatment of N chronic obstructive pulmonary O O O OH disease (COPD), including chronic S bronchitis. S Quaternary ammonium compounds 1- Mandelic acid esters such as Oxyphenonium bromide Clidinium bromide Glycopyrronium bromide  N O N O O OH OH OH Br Br N Br O O O Glycopyrronium bromide Oxyphenonium bromide Clidinium bromide All are aminoalcohol ester of mandelic acid. The distance between the quaternary carbon and ester oxygen is two-carbon (ethyl) bridge. There is bulky carbocyclic group at  carbon of mandelic acid. Clidinium bromide marketed alone and in combination with the minor tranquilizer chlordiazepoxide for the treatment of GIT diseases. It is suggested for peptic ulcer, ulcerative or spastic colon, anxiety states with GI manifestations, nervous stomach, irritable or spastic colon, and others. Glycopyrrolate Glycopyrrolate has atropine-like effects It has a spasmolytic effect on the musculature of the GI tract as well as the genitourinary tract. But used mainly as inhaler alone or in combination for treatment of asthma. Its side effects are typically atropine-like Chemical synthesis of oxyphenonium bromide O O Na2CO3 OH + N N OH HO O OH Benzene CH3Br O OH N Br O Oxyphenonium bromide  Oxybutynin Mandelic acid ester Four-carbon distance O OH Tertiary aliphatic amine O N Protonated inside the body Oxybutynin 4-Diethylaminobut-2-ynyl 2-cyclohexyl-2-hydroxy-2-phenylethanoate By competitively blocking the muscarinic receptors, it has direct spasmolytic effects on bladder smooth muscle. This reduction in smooth muscle tone allows for greater volumes of urine to be stored in the bladder, which results in less urinary incontinence, urgency, and frequency. Quaternary ammonium compounds 2- xanthene derivatives Methantheline and propantheline are mainly antispasmodics and antisecretory agents N N Br Br O O O O O O Methantheline bromide Propantheline bromide Other Quaternary ammonium compounds Umeclidinium HO Br- O N+ 1-(2-(benzyloxy)ethyl)-4-(hydroxydiphenylmethyl)quinuclidin-1-ium bromide Chemically, there is no ester so it has prolonged antimuscarinic effects. It is used as inhalation as a maintenance treatment for chronic obstructive pulmonary disease (COPD)  Miscellaneous HCl O N OH O Cyclopentolate HCl 2-(Dimethylamino)ethyl 2-(1-hydroxycyclopentyl)-2-phenylacetate hydrochloride Chemically, it is an aminoalcohol ester; the terminal amine is tertiary aliphatic so it is protonated at the physiological pH. Used as eye drops for repid cycloplegia and mydriasis.in the management of iritis, iridcyclitis and others.  Dicyclomine HCl O N O Dicyclomine 2-(Diethylamino)ethyl [1,1'-bi(cyclohexane)]-1-carboxylate hydrochloride Chemically, it is an aminoalcohol ester, with tertiary aliphatic amine that is protonated at the physiological pH. Accordingly, its anti-muscarinic effect is much weaker than atropine, however it has more uniform oral bioavailability than atropine. It is used for its spasmolytic effect on various smooth muscle spasms, particularly those associated with the GI tract. It is also useful in dysmenorrhea, pylorospasm, and biliary dysfunction.  Solifenacin Quinuclidine ring, tertiary amine, protonated at physiological pH Tetrahydroisoquinoline O N N O Two-carbon bridge between amine and ester functionality Solifenacin (3R)-1-Azabicyclo[2 2 2]oct-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate Anti-muscarinic with selectivity for the bladder over other tissues. Better selectivity than oxybutynin.  Tolterodine OH N Tolterodine (S)-2-[3-(Diisopropylamino)-1-phenylpropyl]-4-methylphenol Competitive muscarinicantagonist atthebladder muscles,resulting in relaxationof smoothmuscletoneandallowing forgreater volumeof urinetobestored in the bladder. Usedforsymptomatic treatment of anoveractive bladder. Tropicamide Amide group Four-carbon distance between the tertiary amine and amide O functioanlity HO N N Aromatic tertiary amine, partially ionized at Tropicamide physiological pH N-Ethyl-3-hydroxy-2-phenyl- N-(pyridin-4-ylmethyl)propanamide Used as eye drop for mydriasis. Its maximum effect is achieved in about 20 to 25 minutes and lasts for about 20 minutes, with complete recovery in about 6 hours. Its action is more rapid in onset and wears off more rapidly than that of most other mydriatics. Nicotinic antagonists Ganglionic blockers agents that block the action of acetylcholine at autonomic ganglia (sympathetic and parasympathetic). They are non selective and cannot distinguish between sympathetic and parasympathetic ganglia. They can be used as antihypertensive. They are classified to depolarizing and non-depolarizing.  Depolarizing ganglionic blockers induce initial stimulation followed by blocking action, e.g. large dose of nicotine. N N Nicotine  Non depolarizing ganglionic blockers compete with acetylcholine for the nicotinic receptors at the ganglia, e.g. tetramethylammonium bromide, hexamethonium bromide, mecamylamine, and pentolinium bromide. N+ Br- + Br- N Br- N+ N+ N+ Br- Br- Tetraethylammonium bromide Hexamethonium bromide Pentolinium bromide Monoquaternary ammonium salt Bisquaternary ammonium salt Neuromuscular blockers The first compound known to prevent the action of acetylcholine at motor end plate and cause muscle relaxation is curare so it was the prototype for discovery of antinicotinic agents as atropine was for that of antimuscarinic drugs. They are used as adjuncts to general anesthetics during surgery, and to facilitate endotracheal endoscopy or intubation. Non depolarizing competitive neuromuscular blockers O Quaternanry ammonium group N HO O HO O Tertiary amine protonated at H N physiological pH Cl O d- Tubocurarine The distance between two ammonium groups is 10-12 carbon distance. Shorter and longer distances result in decrease in activity. Both ammonium groups bind to the receptor as the nicotinic receptor has two active sites for nicotine binding. So full antagonist requires two ammonium groups with distance from 10-12 carbon atoms  Gallamine N N O O.3I N O Gallamine ssay : non aqueous titration with perchloric acid using crystal violet as indicator  N N Chemical OH OH NaOH O + 3 N synthesis of Cl O OH N O gallamine pyrogallol 3 I N N O O.3I N O Gallamine Steroid based Quaternanry Heart rate and BP Tertiary No significant effects on CVS Intermediate acting neuromuscul O O ar blockers O O - N+ H N+ + Br H N N Br- Br- H H H H O O H H O O Vecuronium bromide Pancuronium bromide Long acting, more potent than tubocurarine Long duration of action O O O H N+ N Br- H H HO H Rocuronium bromide Intermediate acting Atracurium O O O- S O O O O O O O O- O O S N+ O O N+ O O O Atracurium It is useful for patients with hepatic or renal diseases. Depolarizing neuromuscular blockers They depolarize the membrane of muscle end plate giving persistent blockade of the cholinergic receptors. This effect cannot be antagonized by anticholinesterase, but can be antagonized by hexamethonium salt.  Succinylcholine Two acetylcholine molecules linked together O O N+ N+ O O Succinylcholine Distance between the two quaternary nitrogen atoms is 10-carbon atom (14.0 Å) increasing the disatnce leads to reduction in activity till 16 carbon atom (20.0Å) where the activity increases again