Medcnl Chem IIHomeostatc Agnt
Medcnl Chem IIHomeostatc Agnt MDCM 626
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This 20 page Class Notes was uploaded by Kenyon Kessler on Monday September 7, 2015. The Class Notes belongs to MDCM 626 at Kansas taught by Staff in Fall. Since its upload, it has received 64 views. For similar materials see /class/186813/mdcm-626-kansas in Medicinal Chemistry at Kansas.
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Date Created: 09/07/15
Medicinal Chemistry II MDCM 626 Spiing 2006 Homeostatic Agents Sunil A David MD PhD Life Sciences Research Laboratories 145 E Building B 1501 Wakarusa Drive University of Kansas Lawrence KS 66046 Tel 785 8641610 Email sdavidkuedu httpwwwmedchemkuedufacutydavidhtm EXAMINATIONS Sp 1 2 3 0t quizzes Every Wednesday Hour Exam ApIil 19 Wednesday 2048 amp 2049 100150PM Final Exam May 15 Monday 1030 am 100 pm Total points 600 Hour Exams 3 300 Quizzes 100 Final Exam 200 ATTENDANCEEXAM POLICY No Attendance policy No Makeup Exams OTHER POLICIES Disabilities Religious con icts Academic Misconduct KU School of PhaImacy Policies DISCUSSION By Appointment Topics 1 Cholinergics II Adrenergics IIICardiovasculaI Agents Required Text Foye WO Lemke TL Williams DA Principles 0fMedicimll Chemistry 5Lh Ed References Goodman amp Gilman s The Iquot 39 039 39Busis 0fT39 r 39 10Lh Ed Wilson and Gisvold s Textbook of Organic Medicinal and Pharmaceutical Chemistry Edited by Delgado and Remers 10Lh Ed Burger s Medicinal Chemistry and Drug Discovery Vol 15 Edited by Wolff 5 h Ed MDCM 626 Website wwwmedchemkuedumdcm626 Definitions Homeostasis Regulation of physiological processes such that the internal environment of the organism is at equilibrium Autonomic nervous system The component of the CNS Central Nervous System that functions below the conscious level controlling several key physiological processes 2 Regulation of blood pressure Smooth 111115016 3 Control of visceral smooth muscle eyes bladder bowels 4 Control of endocrine and exocrine glands 5 Control of metabolic energy glycolysis neoglucogenesis etc 1 Distribution of blood flow amp tissue perfusion Vascular Definitions contd Ganglion sing Ganglia plur Collection of nerve cell bodies with synapses outside the CNS Synapse Junction between two nerve cells or with endorgan Preganglionic Proximal to before the ganglion Preganglionic Distal to after the ganglion Ciliary Ganglion parasympathetic l Inrwml mmn nl army Uppmztuism of and mom 171m oculomotorneyve l 5mm L 39I39O t Mam root Law aim of anulamolar mm Zygmmdic We Presynaptlc terminal I ACh receptor Acetylcholmesterase Postsynamic terminal Autonomic Nervous System ANS 0 Controls the involuntary bodily functions 0 Provides innervation to the heart glands blood vessels smooth muscles etc 0 SYMPATHETIC and the PARASYMPATHETIC divisions Parasympathetic Axons emerge through the cranial brain and the m tail regions of the spinal chord The ganglia are usually close to or embedded in the target organ 0 Acetylcholine is both preganglionic and postganglionic neurotransmitter Cholinergic Sympathetic Axons originate in the thoracic chest and lumbar lower back regions of the spinal chord The ganglia are usually close to the central nervous system Norgpinephrine mainly and epinephrine in adrenal gland released at the postganglionic neurotransmitters These neurons are also called Adrenergic 39 Acetylcholine is the preganglionic neutrotransmitter in the sympathetic system 39 Afew sympathetics sweat glands and salivary glands have Acetylcholine as the postganglionic neurotransmitter Functionally the two are generally antagonistic The sympathetic division stimulates functions involved in ght or ight reactions fear anger etc whereas the parasympathetic division stimulates more tranquil functions restanddigest Cholinergic Nervous System Acetylcholine neurotransmitter releasing nerve fibres parasympathetic The parasympathetic nervous system innervates both smooth and cardiac muscle as well as exocrine glands Biologic responses to parasympathetic stimulation Constriction of pupil miosis ciliary body accommodation of lens Contraction of smooth muscle in the GI peristalsis and urinary tract Constriction of the bronchioles bronchoconstriction Slowing of heart rate bradycardia Increased secretion by the glands ChOllIlCI glC agonist Agents that bind to acetylcholine receptors and stimulates the parasympathetic system parasympathomimetic Cholinergic antagonist Agents that bind to acetylcholine receptors but exhibit no intrinsic activity parasympatholytic 7 competitive to endogenous Ach Ester Quat amine 2 Me Me HO Me 0 HO N Me NH Acetylcholine ACh Ethanolamine Biosynthesized in cholinergic neurons involving an enzyme catalyzed Choline acetyltrans ferase transfer of acetyl group from acetyl coenzyme A acetyl COA to choline Choline is the limiting factor for acetylcholine biosynthesis Most of the choline is recycled following the enzymatic hydrolysis of acetylcholine in the synaptic cleft Some choline is biosynthesized from the amino acid Serine Choline acetyltransferase ChAT enzyme is biosynthesized in the cholinergic neuron Acetylcholinesterase AChE a serine hydrolase enzyme is responsible for the hydrolysis of acetylcholine to form choline and acetate This hydrolytic inactivation of acetylcholine serves as the physiologic mechanism for terminating its effects Presynapilc terminal ACh rereptor Aczetylchollnesterase C vtic terminal Biosynthesis of Acetylcholine gm gel me CholineN Methyl HO Decarboxylase Ho Tramferase NH COZH 2 SAdenosylmethionine Me donor LSerine Choline Acetyl Me Transferase Me Ho M o 3Me gt e Me Me AcetylS Coenzyme A Acetyl donor 0 Me Choline Acetylcholine Hydrolysis of Acetylcholine Me Acetylcholine Esterase Me o AChE HoeMe Me 9 T N Me gt N Me 0 Me Me T Acetylcholine O Choline Acetate Schema c ofAcetylcholine Biosynthesis Adjon Hydrolysis and Reuptake Cholinergic Neuron Post synapu39c Cell Synapuc Cleft Receptur Respunse Respunse ACh Acetylchulme 07h chulme ChAT Chulmeacetyltransferase AchuA AcetylrSrCuenzymeA 7TM Protein Rhodopsin Model of Ach in muscarinic receptor mcmmlc M 39uounl39 M 39urduc39 u 39gunuuvmmoom muscle39 r acanons CNS canax Hean am Exncnna glands39 7Lung eNs canon ch varylncahsad hlvnocamnus Smoom musc n gasuxc samry nxc smavum uxpmsslan m Glands gaslnc GI Iran Smuum musde 51 subsanha mng szhvaly CNS Mde y mu eye Salivary glands msmmuea am vase Insmany muscle Endmhehum e 3r response y up we J CAMP Inmmuun quot3 Sumnlanan As M1 As M newlansanon Caquot mnaurzlnnce can Excuauon slew K wndumnca 2959 K39 conductance nnal ch excnanon cammc mmmnan Gasmc salwaly Enhanced locamouon Nol knnwn use 7memuly Nuumv Inmhmun 5 mm Gaslm sacvemm CE I al muscanmc smualh musc e en 9 we r wnIricHon M quotma ecuwaocnmmonauun Vasndllnmucn Acn As M As M A M As M camaml Oxolmmnnna mmsaa mmmne mmpme Auupine Alvcplne Alrapme Dicyclavenne39 chydnvenne DICycluvinM chyclavnine Diwclovanne dlmvumine Tu amdma Tu emmne runamdme Tunem ine Tallavmma Oxyb mn Oxyhulynm o u Nn nybulynm o urynin lpvauaplum lpmlmplum lplalroplum lpla vplum Ipraxroglum Galamma Mamba mm MT3 Prrenzepma Mamba loxm M77 Nicotinic Rece lgtors Receptor sites acted upon by nicotine Location Distribution a Preganglionic in the autonomic nervous system sympathetic and parasympathetic H b Neuromuscular Junctions Somatic N c CNS N Characteristics m Ligand gated ion channels modulates Na r K r transport SubTypes N1 somatic and N2 neural Crystal Structure of an AchBinding Protein Reveals the LigandBinding Domain of Nicotinic Receptors Nature 411 pp 269 2001 Cholinergic and Anticholinergic Drugs Can be classified into 0 Muscarinic Agonists Acetylcholinesterase Inhibitors reversible and irreversible Muscarinic Antagonists Nicotinic Antagonists Muscarinic Agon Pharmacological responses to the interaction of cholinergic agonists with muscarinic receptors include 0 Contraction of smooth muscles 0 Vasodilation of vascular system 0 Increased secretion from exocrine glands Decrease in heart rate and force of contraction Constriction of pupil Me 0 eMe N Me 0 Me 9C1 Acetylcholine chloride 0 Prototypical muscarinic and nicotinic agonist but a poor therapeutic agent 0 Chemicalenzymatic instability Low bioavailability poorly absorbed Nonselective action 0 Quick onset and short duration of action 0 E In ocular surgery causes complete miosis in seconds Instilled directly in the anterior chamber M Me 0 e e N Me c1 0 Me Me 6 Methacholine chloride 0 More stable than acetylcholine 0 More selective action muscarinic gt nicotinic Racemic drug S enantiomer more active c 1 Meg Carbachol chloride Potent agonist activity Nonselective Muscarinic Nicotinic Also acts indirectly by promoting ACh release and anticholinesterase Weak activity Increased hydrolytic stability carbamate linkage more stable than ester Uses Topically for glaucoma intraocular for miosis in surgery Side Effects Corneal edema decreased vision HZN o eMe N Me TWA c1 0 Me Me 9 Bethane ol chloride Potent muscarinic agonist Orally effective also administered by subcutaneous injection Increased hydrolytic stability carbamate and steric bulk Stimulant of GI tract smooth muscle and urinary bladder Uses For the relief ofpostsurgical urinary retention and abdominal distention Low toxicity no serious side effecw Should be used With caution in asthmatic patients Me HZN o T aN3 Me o Pilocarpine Pilocarpine 3 va39aquotu o G I Natural product Isolated from the leaves of Pilocarpm jaborandi I Unstable to alkali lactone hydrolysis and bases epimerization at C3 I Available as ophthalmic solution gel tablet and Ocusert delivery system I Systemic effects include copious sweating salivation and gastric secretion I Used in the treatment ofglaucoma and xerostomia dry mouth posterior her Future Muscarinic Agonists Current research interest is focused on developing agents With selective af nity for muscarinic receptors in the brain Potentially useful in the treatment of Alzheimer s disease and other cognitive disorders 5 o N N 00H3 O N 0 w L3 0 0 H3 Arecoline Xenomeline Oxotremorine Acetylcholinesterase Inhibitors AChEI Inhibition of acetylcholinesterase AChE increases the concentration of acetylcholine ACh in the synapse This results in prolonging the action of ACh producing both muscarinic and nicotinic responses There are two types of cholinesterases in humans Acetylcholinesterase AChE and Bu lcholinesterase BuChE Differs in their location in the body and substrate specificity Aceglcholinesterase AChE 0 Associated with glial cells in the synapse Catalyzes the39 39 39 39 of A 39 39 quot serine39 39 0 Inhibition of AChE prolongs the duration of acetylcholine in the junction 0 AChE inhibitors are indirect acting cholinergic agonists AChE inhibitors are useful in the treatment of myasthenia graVis muscular fatigue weakness atony in the gastrointestinal tract and glaucoma Also useful as agricultural insecticides and nerve gas warfare agents Investigational therapy for Alzheimer s disease and other cognitive disorders Butvglcholinesterase BuChE 0 Located in human plasma also called pseudocholinesterase Broader substrate specificity for esters 0 May hydrolyze dietary ester and drug molecules in the blood AChE Mediated Hydrolysis of Ace lcholine HO Me OSen ne OXOV Mea Me O OSerineOH T HMe3 O Acetylcholines teras e Acetylcholine AChE O o 44 i Serine OH H O O i 0Serine O Me H M93 HO Me g Choline Mechanism of ACh Hydrolysis by AChE The catalytic triad Ref A Shafferman et al J Biol Chem 1992 267 1764017648 Reversible Inhibitors i Substrates for and react with AChE forming an acylated enzyme that is capable of hydrolytic regeneration Q ii Binds to AChE with greater af nity than ACh but does not react with the enzyme as substrate 0 MeHN Physostigmine 0 Natural product isolated from the seeds of Physostigma venenosum Sensitive to heat light moisture etc 0 Diffuses into the CNS 0 Antidote for atropine poisoning Topical application in the treatment of glaucoma OTNMeZ j o gMea Neostig mine o NMe2 UT N IllIS Pyridostigmine Chemically more stable than physostigmine Longer duration of action 0 Neostigmine administered orally or iv 0 The most frequent use of neostigmine is to prevent atony of the intestinal skeletal and bladder musculature Also used as urinary stimulant Pyridostigmine is the most widely used AChE for the treatment of myasthenia gravis NHMe O 0 Widely used as an insecticide for use on house plants and vegetables as well for control of eas and ticks on pets Q NMeZEl 9 Edrophonium NH2 I N Tacrine Cognex Administered parenterally Rapid onset and short duration of action Also exhibits direct cholinomimetic effect on skeletal muscle Used in the treatment of myasthenia gravis Potent centrally acting AChE inhibitor FDA approved for the treatment of Alzheimer s Disease To increase ACh levels in the brain Side Effects HepatotoXicity Abdominal cramping Anorexia Nausea Vomiting Diarrhea Irreversible Inhibitors Compounds containing phosphoryl or phosphonic halides that can react with AChE to form AChEphosphate complexes stable to hydrolytic cleavage Mainly used as agricultural insecticides and nerve gas agents Fl 0 OSerineOH o CI T OR OSerineoFOR Acetylcholinesterase OR LR AClLE Aging 0 0 9 H e OSerine O T O MA 1 OSe neO T O 0 OR 6 AChE enzyme not regenerated 0 Me o fo T F OEl P S Me 0 I ANMSS OE 9 Me Me Diisopropylfluorophosphate Ecothiophosphate Inhibits AChE irreversibly 0 Long lasting inhibition up to N 4 weeks 0 Applied topically to the eye in glaucoma treatment Me 0 gt7opF EtO llil CN Me Ills NMez lsopropylmethylPhOSPhono EthylNdimethylphosphor fluoridate Sarin amide cyanidate Tabun 0 Highly potent and irreversible AChE inhibitors 0 Extremely toxic nerve gas 395 cola l i EtO T S lt EtO T ONOZ OB cola OEl alathion Weak AChE inhibitor Weak AChE inhibitor Microsomal Microsomal oxidation oxidation Tl cola ijl EtO P S lt EtO P O lt gt No2 dH 302Et la Malaoxon Paraoxon 10900 tunes more We High AChE inhibitoiy activity AChE inhibitor 0 Bioactivated by microsomal oxidation 0 Main use as agricultural insecticide Malathion is also used in lice infestation 0 Highly poisonous Pralidoxime 2PAM is a mechanism based antidote for poisoning I 0 Effective antidote for poisoning by parathion and related pesticides N 0 Most effective b 39 39 or 0N 0H d y I a m1n1stratlon Me 0 Treatment is effective if initiated within few hours Pralidoxime 2PAM Muscarinic Antagonists 39 quot liliesCholinergic Blockers Aul Agents with high binding af nity for muscarinic receptors but no intrinsic activity 0 Competitive reversible antagonists of ACh Pharmacologic effects opposite of the muscarinic agonists Antagonistic responses include decreased contraction of GI and urinary tract smooth muscles dilation of pupils reduced gastric secretion decreased saliva secretion Therapeutic Uses Treatment of smooth muscle spasms Ophthalmologic examinations Treatment of gastric ulcers Reduction of nasal and upper respiratory tract secretions in cold and u Solanaceous Alkaloids Found principally in henbane Hyoscyamus niger deadly nightshade Atropa belladonna and jimson weed Datum stramom39um Me Me N N H CH20H H CHon 0 x o 0 Belladona Alkaloids Esters of tropic acid and either tropine or scopine Competitive inhibitors 0 Parenteral preparations quarternary derivatives are more potent than the parent compounds 0 Therapeutic Uses Mydriatic Antispasmodic 0 Side Effects Dryness of mouth Urine retention Blurred vision Constipation Atropine is an antidote to poisoning by organophosphorus pesticides Librium a tranquilizer Ph OH o 0 Synthetic drug Administered orally or by parenteral routes Ph 0 Therapeutic Use Treatment of GI disorder in combination with O a I Bra 0 Contraindicated in glaucoma Me Clidinium Bromide O H N CE 0 Synthetic muscarinic antagonist N S 0 Therapeutic Uses Treatment of acidpeptic disease in Japan and Europe 0 Me N 0 Lower incidences of side effects at therapeutic dose 0 Experimental drug in the treatment of chronic obstruction N bronchitis Me Telenzepine 0 Treatment of GI tract spasms dysmenorrhea and biliary WM dysfunction 0 Decreased side effects compared to atropine like agents OH 0 Ph ME 0 Used topically in eye examination Dilation occurs in 0 ME T ME ME 30 min eye returns to normal in 23 hrs Te p 0 Long duration of action Single dose effect can last up to 12 hrs H NltPH 0 Used in the treatment of peptic ulcer adjunctive and other ph conditions of the GI tract associated with hypermotility and hyperacidity 0 Side Effects Dryness of mouth mydriasis dif culty in urination Contraindicated in glaucoma lsopropamlde 92 Methantheline Propantheline Potent anticholinergic agents Propantheline is more potent X5 than methantheline Indicated for gastritis intestinal hypermotility bladder irritability cholinergic spasm peptic ulcer 0 Side Effects Dryness of mouth mydriasis cycloplegia Contraindicated in glaucoma MEN 0 Used in the treatment of early stage Parkinson s disease 0 Adverse Effects Sedation mental confusion in the elderly i 0 Must be used with caution in patients with narrow angle 0 F39h glaucoma Nicotinic Antagonists Agents that bind to cholinergic nicotinic receptors but do not have efficacy Competitive antagonists Two subclasses Skeletal neuromuscular blocking agents and ganglionic blocking agents 0 t4 0M2 HO 0 0H 0 M2N Plant alkaloid Isolated from Chondodendron tomenmsum Causes muscle paralysis arrow poison Rapid onset of action Metocurine is a semisynthetic analog of tubocurarine More potent than the parent compound Therapeutic Use As a muscle relaxant in various surgical procedures 0M2 RH Tubocurarine RMe Metocurine e 0 0 Very short duration of action iv ME NOkYOgwl 0 Rapid recovery fast hydrolysis 0 0 Use Muscle relaxant Suitable for short or long periods Succmylcholme of relaxation Suitable for continuous iv drip Botulinum Toxin Botox Toxin produced by the bacterium Clostridium Botulinum 0 Can grow in improperly processed stored canned foods Causes food poisoning Large doses can be fatal 0 Prevents Acetylcholjne release from the nerve terminal 0 Produces accid paralysis of skeletal muscle Inhibition lasts from several weeks to 3 to 4 months Rigorously purified amp highly diluted for therapeutic use 0 Immunoresistance may develop with continued use Therapeutic Uses Administered locally via intramuscular or intradermal injections to control muscle spasms and to facilitate muscle relaxation eye face neck etc Dermatological Cosmetic Uses 0 To treat facial wrinkles forehead under the eyes etc 0 Prevent excessive sweating palm armpit etc Sales USA 200 Million 2000 350 Million 2002 1 Billion 2005 projected
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