UNIT III_cholinergic neurotransmitter agonist

SPPU Syllabus for Medicinal Chemistry I for B. Pharmacy IV semester students

1. SRP:Cholinergic Neurotransmitter 1 Cholinergic Neurotransmitter Part I Agonist Presented By…. Prof. Sonali R. Pawar Medicinal Chemistry I

2. Cholinergic Neurotransmitter Agonist SRP:Cholinergic Neurotransmitter 2 Syllabus Content

3. 3 Cholinergic neurotransmitters: Biosynthesis and catabolism of acetylcholine. Cholinergic receptors (Muscarinic & Nicotinic) and their distribution. b ) Parasympathomimetic agents: SAR of Parasympathomimetic agents Direct acting agents: Acetylcholine , Carbachol , Bethanechol, Methacholinea Pilocarpine . Part I Indirect acting / Cholinesterase inhibitors (Reversible & Irreversible): Physostigmine, Neostigmine, Pyridostigmine Edrophonium chloride, Donepezil, Tacrine hydrochloride, Isofluorophate Echothiophate Iodide Parathion, Malathion. Cholinesterase reactivator: Pralidoxime chloride.

4. SRP:Cholinergic Neurotransmitter 4 CHOLINERGIC NEUROTRANSMITTERS The  neurotransmitter  acetylcholine (ACh) is the only  neurotransmitter  used in the motor division of the somatic nervous system and the principal  neurotransmitter  at autonomic ganglia. In the CNS, the neurons that release and respond to ACh comprise the  cholinergic  system, which causes anti-excitatory effects. ACETYLCHOLINE It is also the preganglionic neurotransmitter for both the sympathetic and parasympathetic nervous system. Acetylcholine (ACh) is the postganglionic neurotransmitter in the parasympathetic nervous system

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6. SRP:Cholinergic Neurotransmitter 6 Para sympathetic nervous system

7. SRP:Cholinergic Neurotransmitter 7 Nerve impulse Animation - YouTube Anatomy and Physiology - Action Potential Generation and Propagation - YouTube

8. SRP:Cholinergic Neurotransmitter 8 Cholinergic drug , any of various  drugs  that  inhibit ,  enhance , or mimic the action of the  neurotransmitter   acetylcholine , the primary transmitter of nerve impulses within the parasympathetic  nervous system — i.e ., that part of the  autonomic nervous system  that contracts smooth  muscles , dilates  blood vessels , increases bodily secretions, and slows the  heart  rate. Cholinergic fibre means All such fiber that release the acetylcholine as the neuro transmitter A ll the somatic motor neuron to the skeletal muscle A ll preganglionic sympathetic and parasympathetic fibre All the parasympathetic fibre to the neuro- effectors junction Post ganglionic sympathetic fibre to sweat gland

9. SRP:Cholinergic Neurotransmitter 9 Where are cholinergic neurotransmitters found? Acetylcholine  is synthesized in certain neurons by the enzyme choline acetyltransferase from the compounds choline and acetyl-CoA.  Cholinergic  neurons are capable of producing ACh. An example of a central  cholinergic  area is the nucleus basalis of Meynert in the basal forebrain . Is cholinergic the same as acetylcholine? Parts in the body that use or are affected by  acetylcholine  are referred to as  cholinergic . Acetylcholine  is also a neurotransmitter in the autonomic nervous system, both as an internal transmitter for the sympathetic nervous system and as the final product released by the parasympathetic nervous system. The  parasympathetic  nervous system, which uses  acetylcholine  almost exclusively to send its messages, is said to be almost entirely  cholinergic . Biosynthesis and catabolism of acetylcholine

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11. SRP:Cholinergic Neurotransmitter 11 Acetylcholine Synthesis

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14. SRP:Cholinergic Neurotransmitter 14 Cholinergic receptors (Muscarinic & Nicotinic) and their distribution.

15. SRP:Cholinergic Neurotransmitter 15 Biosynthesis and catabolism of acetylcholine

16. SRP:Cholinergic Neurotransmitter 16 What type of receptor is muscuranic receptor? Muscarinic receptors  are G-coupled protein  receptors  involved in the parasympathetic nervous system. The only exception to these  receptors  is the sweat glands, which possess  muscarinic receptors  but are part of the sympathetic nervous system . Eyes : contraction of ciliary muscle and smooth muscle of the iris sphincter ( miosis ) Hear t : Bradycardia (possibly preceded by tachycardia), decrease force of contraction Blood vessel : vasodilation ( EDRF) Lung : bronchoconstriction and increase secretion Pancreas : increased pancreatic juice Urinary bladder : voiding of urine ( detrusor and spincter ) Sweat gland : increased sweating Muscarinic Receptor

17. SRP:Cholinergic Neurotransmitter 17 Muscarinic receptors   are divided into five main subtypes M1, M2, M3, M4, and M5. While each of the subtypes exists within the central nervous system, they are encoded by separate genes and localized to different tissue types. The M1  receptor  is primarily found in the cerebral cortex, gastric, and salivary glands. Nicotinic receptors : In vertebrates,  nicotinic receptors  are broadly classified into two  subtypes  based on their primary sites of expression: muscle-type  nicotinic receptors  and neuronal-type  nicotinic receptors . Nicotinic  acetylcholine  receptors  ( nAChRs ) belong to the “ Cys -loop” superfamily of ligand-gated ion channels that includes GABA A , glycine, and serotonin (5-HT 3 )  receptors .  There  are 16 homologous mammalian nAChR subunits encoded by a multigene family.

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21. SRP:Cholinergic Neurotransmitter 21 Muscarinic Receptor

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24. 24 Nicotinic Receptor What type of receptor is nicotinic receptor? The  nicotinic receptor  is a channel protein that, upon binding by acetylcholine, opens to allow diffusion of cations. The muscarinic  receptor , on the other hand, is a membrane protein; upon stimulation by neurotransmitter, it causes the opening of ion channels indirectly, through a second messenger. Neuro-muscular Junction : nicotinic Nm receptor Stimulation lead to muscle contraction Sympathetic And P. Sympathetic Ganglia : Nn receptor Release of NE and Ach Adrenal Medulla : Nn receptor Release of adrenaline Location of nicotinic receptor: In the adrenal medulla I n the neuromuscular junction of the skeletal muscle I n the central nervous system. In sympathetic and parasympathetic ganglia

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26. SRP:Cholinergic Neurotransmitter 26 Parasympathomimetic A gents . & . Structural Activity Relationship ( SAR) of Parasympathomimetic Agents

27. SRP:Cholinergic Neurotransmitter 27 A  parasympathomimetic  drug, sometimes called a cholinomimetic drug or cholinergic receptor stimulating  agent , is a substance that stimulates the  parasympathetic  nervous system (PSNS). These chemicals are also called cholinergic  drugs  because acetylcholine (ACh) is the neurotransmitter used by the PSNS . These drugs work by mimicking or modifying the effects of acetylcholine (ACh), the primary neurotransmitter of the  parasympathetic  nervous system . Drugs  that activate muscarinic receptors in the peripheral  nervous system  are called parasympathomimetic   drugs  because they  mimic  the effects of acetylcholine on the  parasympathetic nervous system . An example of a parasympathomimetic   drug  is pilocarpine, which is a nonspecific muscarinic agonist. Parasympathomimetic Agents

28. SRP:Cholinergic Neurotransmitter 28 SAR of Parasympathomimetic agents

29. SRP:Cholinergic Neurotransmitter 29 SAR of Parasympathomimetic agents

30. SRP:Cholinergic Neurotransmitter 30 SAR of Parasympathomimetic agents

31. SRP:Cholinergic Neurotransmitter 31 SAR of Parasympathomimetic agents

32. SRP:Cholinergic Neurotransmitter 32 SAR of Parasympathomimetic agents

33. SRP:Cholinergic Neurotransmitter 33 Classification of Parasympathomimetic Agents

34. SRP:Cholinergic Neurotransmitter 34 Therapeutic uses: The drug increases intestinal and bladder motility, which serve as its  therapeutic  action in atony of either organ. Placed topically in the eye, it produces miosis and spasm of accommodation, as well as a lowering of intraocular pressure . It is  used  to treat glaucoma, but pilocarpine is more effective . Drugs that bind to and activate  cholinergic  receptors. A stimulatory alkaloid found in tobacco products that is often  used for  the relief of nicotine withdrawal symptoms and as an aid to smoking cessation.

35. SRP:Cholinergic Neurotransmitter 35 CLASSIFICATION Following 2 ways increase the stimulation of Acetylcholine Receptors ( AChR )

36. SRP:Cholinergic Neurotransmitter 36 Direct Acting

37. SRP:Cholinergic Neurotransmitter 37 Indirect Acting

38. SRP:Cholinergic Neurotransmitter 38 Indirect Acting

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42. SRP:Cholinergic Neurotransmitter 42 ACETYLCHOLINE Acetylcholine:  is acetylcholine is an ester of acetic acid and choline, which acts as a neurotransmitter. It has a role as a vasodilator agent, a muscarinic agonist, a hormone, a human metabolite, a mouse metabolite and a neurotransmitter. It is an acetate ester and an acylcholine . The  mechanism of action of  acetylcholine:  is as a  Cholinergic  Agonist. A neurotransmitter.  Acetylcholine  in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Uses: Acetylcholine  is the chief neurotransmitter of the parasympathetic nervous system, the part of the autonomic nervous system (a branch of the peripheral nervous system) that contracts smooth muscles, dilates blood vessels, increases bodily secretions, and slows heart rate.

43. SRP:Cholinergic Neurotransmitter 43 CARBACHOL Carbachol  is a parasympathomimetic that mimics the effect of acetylcholine on both the muscarinic and nicotinic receptors. This drug is administered ocularly to induce miosis to reduce intraocular pressure in the treatment of glaucoma.  Carbachol  is also used to stimulate micturition by contraction of detrusor muscle . Mechanism of Action Carbachol stimulates both muscarinic and nicotinic receptors through parasympathomimetic action. When it is used in topical ocular or intraocular, it produces effects like miosis and increased aqueous humor outflow . Uses: Miostat ( carbachol  intraocular solution) is a cholinergic agent that reduces the pressure in the eye by increasing the amount of fluid that drains from the eye and is  used to  treat glaucoma by lowering the pressure inside the eye . Synthesis

44. SRP:Cholinergic Neurotransmitter 44 BETHANECHOL Bethanechol is a Parasympathomimetic choline carbamate that selectively stimulates muscarinic receptors without any effect on nicotinic receptors . Unlike acetylcholine,  Bethanechol  is not hydrolyzed by cholinesterase and will therefore have a long duration of action. Mechanism of action: Bethanechol  chloride acts principally by producing the effects of stimulation of the parasympathetic nervous system. It increases the tone of the detrusor urinae muscle, usually producing a contraction sufficiently strong to initiate micturition and empty the bladder. Uses: Used  to treat certain bladder problems such as the inability to urinate or empty the bladder completely due to certain causes (e.g., surgery, bladder muscle problems). It works by helping the bladder muscle to squeeze better, thereby improving your ability to urinate.

45. SRP:Cholinergic Neurotransmitter 45 METHACHOLINE Methacholine  (INN, USAN) (trade name Provocholine ) is a synthetic choline ester that acts as a non-selective muscarinic receptor agonist in the parasympathetic nervous system . Mechanism Of Action: Methacholine  chloride is a cholinergic agonist. Bronchial smooth muscle contains significant parasympathetic (cholinergic) innervation.  Methacholine  chloride agonizes the muscarinic receptors which eventually induce bronchoconstriction. Uses: Methacholine  is used as a test to determine whether you may have asthma. It is a cholinergic drug that causes wheezing and shortness of breath.

46. SRP:Cholinergic Neurotransmitter 46 PILOCARPINE Pilocarpine  is an orally available cholinergic agonist that is used to treat symptoms of dry mouth in patients with keratoconjunctivitis sicca ( Sjögren syndrome) or with xerostomia (dry mouth) due to local irradiation. ( Keratoconjunctivitis sicca  is dryness of the conjunctiva (the membrane that lines the eyelids and covers the white of the eye) and cornea (the clear layer in front of the iris and pupil). Too few tears may be produced, or tears may evaporate too quickly. ) Mechanism Of Action: Pilocarpine  hydrochloride is a direct acting cholinergic parasympathomimetic agent which acts through direct stimulation of muscarinic receptors and smooth muscle such as the iris and secretory glands. Uses: Pilocarpine  is  used  to treat dry mouth caused by radiotherapy in people with head and neck cancer and to treat dry mouth in people with Sjogren's syndrome (a condition that affects the immune system and causes dryness of certain parts of the body such as the eyes and mouth).

47. 47 PHYSOSTIGMINE Physostigmine  is a cholinesterase inhibitor used to treat glaucoma and anticholinergic toxicity. A cholinesterase inhibitor that is rapidly absorbed through membranes. It can be applied topically to the conjunctiva . Mechanism Of Action: Physostigmine  acts by interfering with the metabolism of acetylcholine. It is a reversible inhibitor of acetylcholinesterase, the enzyme responsible for the breakdown of acetylcholine in the synaptic cleft of the neuromuscular junction. It indirectly stimulates both nicotinic and muscarinic acetylcholine receptors. Uses: Physostigmine  salicylate has FDA approval for  use  in the treatment of glaucoma, as well as the treatment of anticholinergic toxicity. It is useful to treat the central nervous system effects of anticholinergic toxicity due to its ability to cross the blood-brain-barrier.

48. SRP:Cholinergic Neurotransmitter 48 NEOSTIGMINE Neostigmine  is a cholinesterase inhibitor used in the treatment of myasthenia gravis and to reverse the effects of muscle relaxants such as gallamine and tubocurarine .  Neostigmine , unlike physostigmine , does not cross the blood-brain barrier . Mechanism of Action : Inhibits the hydrolysis of acetylcholine by competing with acetylcholine for attachment to acetylcholinesterase at sites of cholinergic transmission. It enhances cholinergic  action  by facilitating the transmission of impulses across neuromuscular junctions . Uses :   Neostigmine  is  used  to improve muscle strength in patients with a certain muscle disease (myasthenia gravis). It works by preventing the breakdown of a certain natural substance (acetylcholine) in your body. Acetylcholine is needed for normal muscle function.

49. SRP:Cholinergic Neurotransmitter 49 PYRIDOSTIGMINE Pyridostigmine  is a cholinesterase inhibitor used for symptomatic treatment of myasthenia gravis and congenital myasthenic syndromes and to reverse neuromuscular blockade by nondepolarizing muscle relaxants. Brand Names. Mestinon , Regonol . Mechanism of Action : Pyridostigmine  inhibits acetylcholinesterase in the synaptic cleft, thus slowing down the hydrolysis of acetylcholine. It is a quaternary carbamate inhibitor of cholinesterase that does not cross the blood–brain barrier which carbamylates about 30% of peripheral cholinesterase enzyme . Uses :   Pyridostigmine  is  used  to improve muscle strength in patients with a certain muscle disease (myasthenia gravis). It works by preventing the breakdown of a certain natural substance (acetylcholine) in your body. Acetylcholine is needed for normal muscle function.

50. SRP:Cholinergic Neurotransmitter 50 EDROPHONIUM CHLORIDE Edrophonium Chloride  is the chloride salt form of edrophonium , a short and rapid​-acting cholinesterase inhibitor with parasympathomimetic activity . Mechanism of Action Edrophonium  works by prolonging the  action  acetylcholine, which is found naturally in the body. It does this by inhibiting the  action  of the enzyme acetylcholinesterase. Acetylcholine stimulates nicotinic and muscarinic receptors. When stimulated, these receptors have a range of effects . Uses: Edrophonium  is used as part of a medical test to help diagnose a muscle disorder called myasthenia gravis.  Edrophonium  is sometimes used to reverse the effects of certain medications used to prevent muscle contractions during surgical procedures.

51. SRP:Cholinergic Neurotransmitter 51 TACRINE HYDROCHLORIDE Tacrine  is a member of the class of acridines that is 1,2,3,4-tetrahydroacridine substituted by an amino group at position 9. It is used in the treatment of Alzheimer's  disease. Mechanism of Action The putative principal  mechanism of action  of  tacrine  for Alzheimer's disease is reversible inhibition of acetylcholinesterase (AChE), which thereby slows the breakdown of the chemical messenger acetylcholine (ACh) in the brain.  Tacrine  also inhibits butyryl cholinesterase activity . Uses: Tacrine  is an anticholinesterase drug  used  for the management of Alzheimer's disease symptoms. A centrally active cholinesterase inhibitor that has been  used  to counter the effects of muscle relaxants, as a respiratory stimulant, and in the treatment of Alzheimer's disease and other central nervous system disorders.

52. SRP:Cholinergic Neurotransmitter 52 DONEPEZIL Donepezil  is an acetylcholinesterase inhibitor used to treat the behavioral and cognitive effects of Alzheimer's Disease and other types of dementia. Mechanism of Action: Donepezil  binds reversibly to acetylcholinesterase and inhibits the hydrolysis of acetylcholine, thus increasing the availability of acetylcholine at the synapses, enhancing cholinergic transmission. Uses: Donepezil is used to treat dementia (a brain disorder that affects the ability to remember, think clearly, communicate, and perform daily activities and may cause changes in mood and personality) in people who have Alzheimer's disease (AD; a brain disease that slowly destroys the memory and the ability to think, learn, communicate and handle daily activities). 

53. SRP:Cholinergic Neurotransmitter 53 ISOFLUOROPHATE Diisopropyl fluorophosphate (DFP) or Isoflurophate is an oily, colorless liquid with the chemical formula C 6 H 14 FO 3 P. It is used in medicine and as an organophosphorus insecticide. It is stable, but undergoes hydrolysis when subjected to moisture . Mechanism of Action : Isoflurophate  is an organophosphorus compound that acts as an irreversible cholinesterase inhibitor. As such, it displays parasympathomimetic effects.  Isoflurophate  is used in the eye to treat certain types of glaucoma and other eye conditions, such as accommodative esotropia . Uses : Isoflurophate  is used in the eye to treat certain types of glaucoma and other eye conditions, such as accommodative esotropia . They may also be used in the diagnosis of certain eye conditions, such as accommodative esotropia .

54. SRP:Cholinergic Neurotransmitter 54 ECHOTHIOPHATE IODIDE Echothiophate Iodide  is the  iodide  salt form of  echothiophate , a long-acting cholinesterase inhibitor with parasympathomimetic activity.  Echothiophate iodide  potentiates the action of endogenous acetylcholine by inhibiting acetylcholinesterase that hydrolyzes acetylcholine . Mechanism Of Action Echothiophate  is an indirect-acting parasympathomimetic agent. By interfering with the enzymatic destruction of acetylcholine,  echothiophate  potentiates the  action  of acetylcholine at cholinergic synapses. The pupil of the eye is constricted by contraction of the iris sphincter, producing miosis . Uses: Echothiophate iodide  ophthalmic (for the eyes) reduces pressure in the eye. This medicine is  used  to treat chronic open-angle glaucoma, and other types of glaucoma, especially after cataract surgery. This medicine is also  used  to treat certain eye-focusing disorders.

55. SRP:Cholinergic Neurotransmitter 55 PARATHION Parathion  is a deep brown to yellow liquid with a faint odor of garlic. It is an organic phosphate insecticide which acts as an inhibitor of cholinesterase, and as such it is highly toxic by all routes of exposure. It may be found as a liquid or as a dry mixture where the liquid is absorbed onto a dry carrier . Mechanism Of Action Parathion  is a cholinesterase inhibitor. It generally disrupts the nervous system by inhibiting acetylcholinesterase. It is absorbed via skin, mucous membranes, and orally. Absorbed  parathion  is rapidly metabolized to paraoxon , as described in Insecticidal activity . Uses: Parathion  is a potent organophosphate pesticide. It is a pale yellow-to-brown liquid with an odor like garlic. It is  used  by farmers as a pesticide on fruits, vegetables, nuts, and grains. Commercial pesticides often contain a hydrocarbon solvent, which itself can cause illness

56. SRP:Cholinergic Neurotransmitter 56 MALATHION Malathion  is a man-made organophosphate insecticide that is commonly used to control mosquitoes and a variety of insects that attack fruits, vegetables, landscaping plants, and shrubs. It can also be found in other pesticide products used indoors and on pets to control ticks and insects, such as fleas and ants . Mechanism Of Action Malathion  exerts its  action  on the nervous system of the lice by irreversibly inhibiting the activity of cholinesterase, thereby allowing acetylcholine to accumulate at cholinergic synapses and enhancing cholinergic receptor stimulation. This eventually leads to the head lice's death . Uses: Malathion  lotion is used to treat head lice (small insects that attach themselves to the skin) in adults and children 6 years of age and older. It should not be used in infants and children younger than 2 years of age.  Malathion  is in a class of medications called pediculicides . It works by killing lice.

57. SRP:Cholinergic Neurotransmitter 57 CHOLINESTERASE REACTIVATORS Cholinesterase reactivators Definition: A drug used to reverse the inactivation of  cholinesterase  caused by organophosphates or sulfonates . Cholinesterase reactivators  (oximes) should be theoretically effective as an antidote for OP poisoning. Oximes work by removal of the phosphoryl group from the inhibited AChE enzyme, resulting in enzyme reactivation . Pralidoxime (PAM) is the most commonly used oxime worldwide . What is the function of cholinesterase? Cholinesterase  is a family of enzymes that catalyzes the hydrolysis of the neurotransmitter acetylcholine (ACh) into choline and acetic acid, a reaction necessary to allow a cholinergic neuron to return to its resting state after activation.

58. SRP:Cholinergic Neurotransmitter 58 Pralidoxime  is a  cholinesterase reactivator  used to treat organophosphate poisoning.  Pralidoxime  is an antidote to organophosphate pesticides and chemicals. Organophosphates bind to the esteratic site of  acetylcholinesterase , which results initially in reversible inactivation of the enzyme . Mechanism of action: The principal action of  pralidoxime is  to reactivate  cholinesterase  (mainly outside of the central nervous system) which has been inactivated by phosphorylation due to an organophosphate pesticide or related compound.

59. SRP:Cholinergic Neurotransmitter 59 CHOLINESTERASE

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61. SRP:Cholinergic Neurotransmitter 61 AchE Inhibitor

62. SRP:Cholinergic Neurotransmitter 62 AchE Inhibitor

63. SRP:Cholinergic Neurotransmitter 63 AchE Inhibitor What are acetylcholinesterase inhibitors used for? To treat neuropsychiatric symptoms of diseases such as Alzheimer's disease, particularly apathy . To increase chances of lucid dreaming (by prolonging Rapid eye movement sleep   REM sleep) To treat Alzheimer's disease, the Lewy body dementias and Parkinson's disease.

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