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Medicinal Chemistry 745
Medicinal Chemistry 745
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Ashok Philip, Ph.D. Assistant Professor of Pharmaceutical Sciences 731-661-5704 (office) firstname.lastname@example.org Parkinson?s Disease 1. Wilsons and Gisvold?s Textbook of Organic Medicinal and Pharmaceutical Chemistry, 12th Edition, Copyright ©2011 Lippincott Williams & Wilkins 2. FOYE?s Principles of Medicinal Chemistry, 6th Edition, Copyright ©2008 Lippincott Williams & Wilkins 3. Drug Labels accessed from: http://dailymed.nlm.nih.gov/dailymed/about.cfm 4. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy (2nd edition) Golan et. al; Lippincott Williams & Wilkins, 2008 5. Goodman and Gilman?s The Pharmacological Basis of Therapeutics, 12th Ed. Laurence L Brunton, John S. Lazo, and Keith L Parker, Eds. New York: McGraw-Hill, 2006. Reference Books: Goal: To provide students with the medicinal chemistry perspective of drugs for the treatment of Parkinson?s disease LECTURE 14 Objectives: Students should be able To discuss pathophysiology of Parkinson?s disease To outline drugs effective in the therapy of Parkinson?s disease To understand the metabolic pathways responsible for Parkinsonism by MPTP To outline the utility of L-DOPA therapy in treating Parkinsonism To outline various drug classes used for the treatment of Parkinsonism To understand the chemical composition of drugs and the SAR of drugs used the treatment of Parkinsonism Parkinson?s Disease (PD) Progressive neurodegenerative disorder due to loss of pigmented dopaminergic neurons in pars compacta region of substantia nigra A9 cell bodies in substantia Nigra & nerve terminals in Striatum degenerated Parkinson?s Disease (PD) Characterized by: Bradykinesia Tremors Muscular rigidity Postural Imbalance Appearance of intracellular inclusions ? Lewy Bodies DA: Synthesis, Metabolism, Receptors Tyrosine hydrolase (TH) Aromatic amino acid decarboxylase (AADC) DA transporter (DAT) NE transporter (NET) Monoamine oxidase (MAO) Aldehyde dehydrogenase (ALDH) Catechol-O-methyl tranferase (COMT) Homovanillic acid (HVA) Phenylalanine hydroxylase (PH) DA: Synthesis, Metabolism , Receptors L-Tyrosine Levodopa Dopamine Parkinson?s Disease (PD) - Pharmacotherapy 1. Levodopa/Carbidopa Products Sinemet®, Sinemet CR®, Parcopa®, Stavelo® Lodosyn® (Carbidopa only) 2. MAO-B Inhibitors - Selegiline (Eldepryl®) - Rasagiline (Azilect®) 3. COMT Inhibitors - Tolcapone (Tasmar®) - Entacapone (Comtan®) Parkinson?s Disease (PD) - Pharmacotherapy 4. Dopamine Agonists - Bromocriptine (Parlodel®) - Ropinirole (Requip®) - Pramipexole (Mirpex®) - Apomorphine (Apokyn®) 5. Anticholinergics - Trihexyphenidyl 6. Amantadine (Symmetrel®) - Benztropine (Cogentin®) 1. Levodopa/Carbidopa Products Levodopa Dopamine L-aromatic amino acid decarboxylase Result: L-DOPA converted to Dopamine in PERIPHERY rather than in BRAIN - Levodopa can cross BBB (DA cannot) - Levodopa converted in CNS by AADC Big Problem: Levodopa metabolized by MAO-A (in GI Tract) and by AADC (in Periphery) Solution: Carbidopa 1. Levodopa/Carbidopa Products S(-)-Carbidopa - A peripheral AADC inhibitor - Markedly increases proportion of L-DOPA that crosses BBB - Does not cross BBB 2. MAO-B Inhibitors - Propargylamine derivatives - Selective irreversible inhibitors of MAO-B at low to moderate doses - Extend the duration of response to L-DOPA ? By reducing metabolism of dopamine - Both metabolized by N-dealkylation, Hydroxylation R-(+)-Rasagiline R(-)- Selegiline (Eldepryl®) R(+)-Rasagiline (Azilect®) 2. MAO-B Inhibitors R(-)- Selegiline (Eldepryl®) N-dealkylation + + 3. COMT Inhibitors Reversible inhibitors of COMT Block peripheral conversion of L-DOPA to 3-O-methyl DOPA Tolcapone: Longer duration of action Entacapone: Shorter duration of action Tolcapone: Fatal hepatic failure observed in 3 cases, restricted use Tolcapone (Tasmar®) Entacapone (Comtan®) 4. Dopamine Agonists An Ergot-peptide derivative Partial agonist at D1-type Full agonist at D2-type Low doses ? Prolactin inhibitor High doses ? Antiparkinsonism effects Usually given in combination with L-DOPA therapy Bromocriptine (Parlodel®) 4. Dopamine Agonists Both are non-ergot compounds Full agonists at D2 and D3 receptors Orally active compounds indolinone thiazole Ropinirole (Requip®) Pramipexole (Mirpex®) Stimulates dopamine receptors and produces effects similar to dopamine 4. Dopamine Agonists Apomorphine (Apokyn®) Dopamine 5. Anticholinergics (±) Trihexyphenidyl Benztropine (Cogentin®) - Modest antiparkinsonian activity - Used widely before Levodopa therapy 6. Amantadine (Symmetrel®) - Promotes DA release in Striatum - Exhibits anticholinergic properties - Also blocks NMDA glutamate receptors - A 1° amine & exists in protonated form at physiological pH - So how does it enter the brain? Cage structure increases lipophilicity - Cage structure also avoids catabolism by oxidative enzymes
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