Class Note for MDCM 626 at KU
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Date Created: 02/06/15
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 Spot quizzes Every Wednesday 1 2 3 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 0fMedicinal Chemistry 5Lh Ed References Goodman amp Gilman s The Pharmacological Basis of Therapeutics 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 1 Distribution of blood flow amp tissue perfusion VaSCUIar 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 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 l Illicrml mmtill army Upper divisian of and carolid 17lqu oczzlomotm neyvc Sammy root Motor mot Lower mm of anulamatar mama Zygumam nane Presynaptic terminal ACh receptor Acetylcholinesterase Postsynaptic 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 sacral 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 0 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 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 Presynaptic terminal Acetylchollnesterase wapiic terminal Biosynthesis of Acetylcholine gm gel me CholineN Methyl HOE Decarboxylase Ho Tramferase NH COZH 2 SAdenosylmethionine Me donor LSerine Choline Acetyl Me Transferase Me Ho Me 0 3Me Me AcetylS Coenzyme A Acetyl donor 0 Me Choline Acetylcholine Hydrolysis of Acetylcholine Acetylcholine Esterase Me OweM9 AChEgt H0eMe Me 8 N Me gt N Me 0 Me n Me O Choline Acetate Schema c ofAcetylcholine Biosynthesis Adjon Hydrolysis and Reuptake Cholinergic Neuron Post synapu39c Cell Synapuc Cleft El 0 112 Caz Receptur Respunse Fymvate ACh ACh AchuA ACh ACh Glucuse chm AchACh Assay ACh Ach Ch ChE Cha ng Respunse ACh Acetylchulme 07h chulme ChAT Chulmeacetyltransferase AchuA AcetylrSrCuenzymeA 7TM Protein Rhodopsin Model of Ach in muscarinic receptor emclolllln M 39uounl39 M39urd lc39 u ull M 39glnnuulmmooln muscle39 7 ecallons CNS canaxl Haan eme Exncllna glands39 7Lung CNS39co oxl chverylucellseu hIDDOCamnus Smooln muscle easlvlc salwm um slnalum uxprssslan ln Glands Qasmcu GI lvan l Smuum muscle GI sueslenlle mgm Szhvaly 2k ch wlde y ml eye sallvary glands elslnnulea Blood vessels Insclllely muscle enecmellum e er response l w DAG JcAMP lmumllen l IFJSHmulannn A5 M2 As MJ Dawlansallan l Caquot oonauelence l ceavl Exalmllon lslew l K39wndumanca 99st K39 cuneuelanee mm CNS mllallon Caldlnc mlulzlllen Gaakic salivary Enhanced locnmmlon Nol knnwn quot5a 7memely Neulal lnruelllen seclellon Gaslm secrelum eenlral museennlc cl smoum muscle elleclsl e e Hemoh eonllecllon hypmhermla Oculm ammmodaliun Vamdllmallcn gt5 mm As Mk As M A M As M swedlve Camachal Oxolremnnna Memm Almplne Almplne Auepine Almpine Awopine Dicyclavenne uncyclovenne chyclevema chycluvanne Dicyclovanne dimlnmmeb Tu emd39lna Tellemuine rullemelne Yullem ine Tallemume Oxybufymn Oxyhulynm oxynulymn nybulynln Oxybutymn lplalreplum lpmlrepmm lpralmplum lplelmplum lemmequot Galamma Mamba tom M73 Plrenzepme Mamba loxlll M17 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 NMe o M e 6 Cl 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 Me 0 ampMe 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 c1 HZN O93Me T N Me 0 Me 9 Carbachol chloride Potent agonist activity Nonselective Muscarinic Nicotinic Also acw indirectly by promoting ACh release and anticholinesterase Weak activity Increased hydrolytic stability carbamate linkage more stable than ester Topically for glaucoma intraocular for miosis in surgery Side Effects Corneal edema decreased vision M HZN 0 ea 9 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 For the relief of postsurgical urinary retention and abdominal distention Low toxicity no serious side effecw Should be used With caution in asthmatic patients Pilocarpine 9Wquot 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 chamber 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 N N OCH O N N N O IEH3 Arecoline Xenomeline Oxotremorine 0 H3 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 rylcholinesterase BuChE Differs in their location in the body and substrate specificity Ace lcholinesterase AChE 0 Associated with glial cells in the synapse Catalyzes the hydrolysis of Acetylcholine serine hydrolase Inhibition of AChE prolongs the duration of acetylcholine in the junction 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 Acetvlcholine HO Me Me OSen ne O o 3 Me O OSerineOH T HMe3 O Acetylcholinesteras e Acetylcholine AChE O o O Serine OH i HO i H0 Serine O Me HO Me O W93 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 OTNMeZ o I 0 o N NMea Allle 9 Pyridostigmine Chemically more stable than physostigmine Longer duration of action 0 Neostigmine administered orally or iv 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 O CO vegetables as well for control of eas and ticks on pets OH 0 Administered parenterally 0 Rapid onset and short duration of action 0 Also exhibits direct cholinomimetic effect on skeletal muscle gMeZE 0 Used in the treatment of myasthenia gravis Edrophonium NH2 0 Potent centrally acting AChE inhibitor 0 FDA approved for the treatment of Alzheimer s Disease I To increase ACh levels in the brain N 0 Side Effects HepatotoXicity Abdominal cramping Anorexia Nausea Vomiting Diarrhea Tacrlne Cognex 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 OR AChE Aging TI TI 9 e OSerine O T O amp OSen39neO T O 0 OR 6 AChE enzyme not regenerated 0 O P F l OEl P S Me 0 I NMea A 0a 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 0 o gt7oF EtO llii CN Me Me NMe2 IS Pr Pylquot EthVIPhOSPhOVIO EthylNdimethylphosphor fluoridate Sarin amide cyanidate Tabun 0 Highly potent and irreversible AChE inhibitors 0 Extremely toxic nerve gas cola EtO P S lt I cola CB 8 BO T ONOZ OEl Malathion Parathion Weak AChE inhibitor Weak AChE inhibitor Microsomal Microsomal oxidation oxidation Tl cola ijl EtO P S lt EtO P 04ltigt w2 dH 302Et la Malaoxon Paraoxon 10000 times more active High AChE inhibitory 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 by intramuscular intravenous or subcutaneous 9quot OH administration Me 0 Treatment is effective if initiated within few hours Pralidoxime 2PAM Muscarinic Antagonists AnticholinergicsAn muscarinicsCholinergic Blockers 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 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 OH 0 Synthetic drug Administered orally or by parenteral routes Ph 0 Ph 0 Therapeutic Use Treatment of GI disorder in combination with O 9T Ere Librium a tranquilizer 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 C j 0 Experimental drug in the treatment of chronic obstruction T 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 9Nlt 0 Used in the treatment of peptic ulcer adjunctive and other 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 O OH 8 O OH 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 W O blocking agents Ho k 0 0 Plant alkaloid Isolated from Chondodendron tomenmsum 0 Causes muscle paralysis arrow poison 0 0 Rapid onset of action 0 Metocurine is a semisynthetic analog of tubocurarine More potent than the parent compound M2N 0 Therapeutic Use As a muscle relaxant in various surgical procedures RH Tubocurarine RMe Metocurine e 0 0 Very short duration of action iv ME NokYOgwl 0 Rapid recovery fast hydrolysis 0 Use Muscle relaxant Suitable for short or long periods 0 Succinylcholine 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 0 Causes food poisoning Large doses can be fatal 0 Prevents Acetylcholjne release from the nerve terminal 0 Produces accid paralysis of skeletal muscle 0 Inhibition lasts from several weeks to 3 to 4 months 0 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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