Autonomic Nervous System, Assignments of Pharmaceutical Chemistry

Download Autonomic Nervous System and more Assignments Pharmaceutical Chemistry in PDF only on Docsity! Advanced Medicinal Chemistry (MPC 103T) ASSIGNMENT TOPIC – Adrenergic & Cholinergic Agents Session – 2020-21 SUBMITTED TO - SUBMITTED BY- Prof. N.S. Hari Narayana Moorthy RAM RUDRA SAHU (Dept of pharmacy) M.Pharmacy 1st sem. (Pharma. Chem.) Divisions of human hervous system Nervous system Heart Depress (LHR, +Conduction) Stimulate (THR, TConduction) B Bronchus Stimulate (Bronchoconstriction) Relax (Bronchodialtion) mulate (T movement) Relax (movement) GIT Bladder e Stimulate (7 Urine out flow) Relax (LUrine outflow) Stimulate (Miosis) Relax (Mydriasis) Pupil Glands Stimulate (Tse secretion) Depress (se secretion except sweating) Sympatretic Parasympathetc Eve > Salivary glands > Whoract= Genitals > — Sympathetic alls sqroiia -+) Eve  SAR (Structural Activity Relationship) -  Modification in Quaternary Ammonium Group -  Methyl groups substituted with higher alkyl groups are inactive as agonist .  If all methyl groups are ethylated it shows antagonistic activity .  The +ve charge is necessary for its activity .  If all methyl group are replaced by H ion it losts its activity.  Modification in Ethylene Bridge –  Introduction of alkyl group will rapidly reduce activity .  Rule of five : Ing postulated that there should not be more than five atom b/w N and the terminal H atom for maximal activity .  Introduction of methyl group on the Beta C forms Methacholine .  Introduction of methyl group on the Alpha C will leads to less active compound .  Addition of one or two ethyl group will form chiral molecules .  Modification in Acyl group –  When methyl group is substituted with primary amine it results into more POTENT compound .  If ester functional group is substituted with ether or ketone functional group more POTENT compound is formed .  Substitution of acyl group with aromatic or higher molecular weight ester gives ANTAGONIST activity instead of AGONIST activity .  MOA (Mechanism Of Action) – Based on Cholinergic receptors – MUSCARINIC RECEPTOR – These are the Ach receptors that forms Activation of Phospholipase C G-protien complexes in the cell membrane . Hydrolysis of phosphatidyl inositol biphosphate (PIP2) The complex formation of Even no.(M2,M4) muscarinic receptor Inositol triphosphate (IP3) Diacylglycerol (DAG) with G-protein causes :- 1. Inhibiton of adenylcyclase activity . Provokes the release of Ca++ 2. Activation of K+ channels . From endoplasmic reticulum Activates protein kinace C 3. Modulation of Ca++ channels . Excitation NICOTINIC RECEPTORS – These are the Ligand gated ion channels through which Ca++, Na++, K+ can flow . Neurotransmitter regulate the opening and closing of the channels . Therapeutic uses of Cholinergic Agonist – Nicotinic agonists - • Treatment of myasthenia gravis . • Lack of acetylcholine at skeletal muscle causing weakness . Muscarinic agonists - • Treatment of glaucoma . • Switching on GIT and urinary tract after surgery . • Treatment of certain heart defects. Decreases heart muscle activity and decreases heart rate .  Anticholinergic Agents :- • Natural alkaloids- Atropine (spasmolytic, mydriatic), Hyoscine (Scopolamine), Scopoderm TTS (antiemetic). • Semisynthetic derivatives-Mydriatics: Homatropine, GI spasmolytics: Hyoscine butyl bromide. • Synthetic compounds-GI spasmolytics: Oxyphenonium . • Antiulcer drugs: Pirenzepine (M1-blockers). • Antiasthmatics: Ipratropium and Tiotropium. • Antispasmodic: Fluvoxate, Oxybutynin, Trospium. • Mydriatics: Tropicamide . • Antiparkinsonism (central M-cholinolytics): Benztropine, Biperiden, Trihexyphenidyl.  Nicotinic Antagonists – R=H Tubocurarine - As a muscle relaxant in various surgical Procedures (Only one Quaternary ammonium group). R=CH3 Metocurine - Semi-synthetic analog of tubocurarine. A bis-quaternary ammonium compound, it is about four times more potent than the parent compound . (B). SYMPATHETIC SYSTEM :- 1. Sympathomimetics Agents :- Also known as Adrenergic stimulants ; Neurotransmitter are – Adrenaline, Noradrenaline, Dopamine. Biosynthesis precursor – L – tyrosine (L-Tyrosine Hyroxylaze is the rate limiting enzyme in this pathway ). Mechanisms of termination: Metabolized by MAO and COMT enzyme in liver. (COMT (Catecholamine O-methyl transferase)) SAR Adrenaline HO HO NH2 OH H Noradrenaline HO HO H N OH H HO HO OH NH2 COMT O HO OH NH2  Mechanisms of action  SAR – What effect would an antagonist alone have on receptor activation? Phenoxybenzamine (Dibenzyline) Phentolamine (Regitine) N NH3CO H3CO NH2 N N R O O O O O Prazosin: R = Terazosin: R = Doxazosin: R = Quinazoline ring Piperazine ring Acyl moiety (Minipres) (Hytrin) (Cardura) Yohimbine (Yocon) ) Nadolol (Corgard) O N H OH C CH3 CH3 CH3 N S NN O Timolol Pindolol (Visken) Labetalol (Normodyne, Trandate) Carvedilol (Coreg) Atenolol (Tenormin) R OH O N H CH CH3 CH3 Metoprolol (Lopressor, Toprol) R= CH2 Bisoprolol (Zebeta) R= O O CH3 CH2 CH2 O CH CH3 CH3  Synthesis of Parasympathetic & Sympathetic Drugs :- 1. Bethanechol Chloride - 2. 4. Tropicamide - 5. 3. Dicyclomine 5. Succinyl Choline Chloride - Cl HO COCl2 Cl O O Cl Cl O O NH2 N(CH3)3 N O O NH2 Cl 6. Phenoxybenzamine - 9. HN on on + | Me ~ % PA soc; ° cl \ \_{ —> OU CO, OM, 7. Carvedilol - K NooH a <I> o HO oS H iN 4-nydroxy- epichioro— carbarote hydra H.c—o xD dighyme r + ——eere HgN~_—~o 2-(2-methoxypmren— oxyjethylamine 4-(2.3-epoxypropoxy)— cerborote (1) H ba. ae ae eee H o. Ny Carvedilol