11777 - Medicinal and Toxicological Chemistry 2

Course Unit Page

SDGs

This teaching activity contributes to the achievement of the Sustainable Development Goals of the UN 2030 Agenda.

Good health and well-being

Academic Year 2021/2022

Learning outcomes

Students acquire the ability to understand the drug molecular mechanism of action, in particular the role of steric factors and bonds involved in the drug-target interaction; they learn about the main classes of drugs interacting with both cellular targets and neurotransmitter receptors, their chemical-physical properties and structure-activity relationships. They acquire the ability to apply their knowledge to understanding general synthetic methods, the therapeutic use and chemical-toxicological aspects of drugs.

Course contents

Module 1: general part, drugs interacting with autonomic nervous system and histaminergic receptors- Prof.ssa Alessandra Bisi

GENERAL PART

Receptors, drug-receptor complex, receptor activation, principles of receptor theory. Competitive and non-competitive antagonism. Inverse agonism.

SPECIAL PART

Cholinergic system: Acetylcholine: biosynthesis, metabolism, structure activity relationships (SAR). Cholinergic receptor subtypes and neurotransmitter-receptor complexes.

Muscarinic agonists: SAR of muscarine.

Muscarinic antagonists: SAR of atropine and related derivatives. SAR of synthetic compounds. Mode of action. General synthesis of esters. Selective antagonists for receptor subtypes: SAR and synthesis of pirenzepine, methoctramine.

Nicotinic agonists: SAR of nicotine and related compounds.

Nicotinic antagonists. Ganglionic blocking agents: mode of action, SAR, synthesis of pempidine. Neuromuscular blocking agents: SAR, synthesis of succinylcholine, pancuronium.

Cholinesterase inhibitors: mechanism of acetylcholine hydrolysis. Carbamates and reversibile cholinesterase inhibitors (Physostigmine, tacrine, donepezil), SAR. Synthesis of carbamates: neostigmine/edrophonium, synthesis of tacrine. Irreversible inhibitors: structure and SAR.

Adrenergic system: Catecholamines: biosynthesis, metabolism, structure activity relationships (SAR). Catecholaminergic receptors subtypes.

Alpha-adrenergic agonists: Phenylethylamines, imidazolines: mode of action, SAR. Nasal and ophthalmic decongestant. Appetite suppressants, Amphetamine and Ephedrine: mode of action, SAR, synthesis of catecholamines (adrenaline, ethylefrine), synthesis of clonidine.

Alpha-adrenergic antagonists. SAR of indolic alkaloids, ergot alkaloids, imidazoline derivatives, quinazoline derivatives (synthesis of prazosin), benzodioxane derivatives, haloalkylamines, tetramine disulphydes.

Beta-adrenergic agonists. Discovery, development, SAR, synthesis of terbutaline, salbutamol.

Beta-adrenergic antagonists. Discovery, development, stereochemistry, SAR arylethanolamines and aryloxypropanolamines.

Histamine and antihistaminic: histamine: structure, biosynthesis and metabolism, SAR, histamine receptors subtypes, agonists.

Histamine receptor H1 antagonists: general structures. Ethylendiaminic derivatives, SAR, Synthesis of tripelenamine; ethanolaminic derivatives, SAR, Synthesis of diphenhydramine; propilaminic derivatives, SAR synthesis of chlorphenamine. Second and third-generation antihistamines.

Histamine release inhibitors: sodium cromoglycate, structure, SAR.

Histamine receptor H2 antagonists: development, imidazole derivatives: SAR, synthesis of cimetidine; dimethylaminofuranic derivatives: SAR, synthesis of ranitidine; SAR of guanidinothiazole derivatives and piperidinomethylphenoxy derivatives. SAR of diarylic compounds

Antisecretory agents: omeprazole, SAR and mode of action.

Module 2: Drugs acting on cardiovascular system- Prof. Alberto Leoni

Drugs used in heart failure

1. Cardioactive (digital) glycosides: chemistry of cardioactive glycosides. Derivatives of the digital. Strophan derivatives. Derivatives of the scilla. Derivatives of thevetia. Mechanism of action of cardioactive glycosides.

2. The sueprfamily of phosphodiesterases. Pyrimidinone inhibitors (Amrinone, Milrinone). Non-pyrimidinone inhibitors. Phosphodiesterase inhibitors for erectile dysfunction. Development of sildenafil.

Calcium antagonists

Voltage-dependent calcium channels (voc): classification. Effects induced by calcium antagonist drugs. ADME. Action mechanism. SAR.

The calcium antagonist drugs:

a) 1,4-dihydropyridine: nifedipine and related compounds.

b) benzothiazepine: diltiazem.

c) phenylalkylamines: verapamil, gallopamyl.

Antianginal drugs

Classification of angina pectoris and therapeutic approaches.

a) Nitrates and organic nitrites: Nitroglycerin, Isoamyl nitrate, Isosorbide dinitrate, Erythrityl tetranitrate, Pentaerythritol tetranitrate. Mechanism of action of nitroderivatives. Molsidomina.

b) Coronodilators: Dipyridamole, Hydralazine and derivatives, Khellin derivatives: with benzofuran structure (amiodarone), with a chrominic structure (Eflossato, Carbocromene)

c) Potassium channel activators: benzopiranes, discovery of cromakalin, SAR, cyanoguanidine (pinacidil), thioformamides (aprikalim).

d) Calcium antagonists and β-antagonists used in the treatment of angina

Diuretics

Osmotic diuretics, sulfonamide diuretics, carbonic anhydrase inhibitors, xanthine diuretics. Thiazide diuretics: SAR, Chlorothiazide, Hydrochlorothiazide, Meticotiazide, Trichlorometiazide, Idroflumetazide, Bendroflumetazide, Indapamide. Chlorthalidone. Derivatives of sulfamoylbenzoic acid: examples, SAR, furosemide synthesis. Unsaturated alpha-beta carbonyl derivatives: SAR, ethacrynic acid. Potassium-sparing diuretics: antialdosterones: SAR, spironolactone; EnaC blockers: amiloride, triamterene, SAR.

Lipid-lowering drugs

Notes on lipid metabolism. General aspects of the transport mechanisms of lipid dyslipidemia.

Drugs that reduce hypertriglyceridemia: fibrates (clofibrate), nicotinic acid (niacin).

Drugs that reduce hypercholesterolemia: statins, bile acid-binding resins, ezetimibe, probucol. First/fourth generation statins.

Antidiabetic drugs

Insulin and related compounds

Sulfonylureas of first, second and third generation, examples.

Glinids: Meglitinide and related compounds

Drugs acting on the incretin system: hormone GLP-1 analogues (Exenatide, Liraglutide); DPP-4 enzyme inhibitors (Vildagliptin and related compounds)


Αlpha-glucosidase inhibitors: Acarbose, Voglibose, Miglitol

Thiazolidinediones: Ciglitazone and related compounds.

Licorice extract: Amorfrutina 2, Amorfrutin B

Module 3: Drugs interacting with intracellurar receptors- Prof.ssa Maria Laura Bolognesi

Steroid hormones: Structure, biosynthesis, steroid receptors:

Estrogens: structures, SAR, natural and synthetic estrogens, synthesis of diethylstilbestrol.

Estrogen receptor modulators: receptor antagonists, triphenylethylamine derivatives, tamoxifen, raloxifene and related compounds, SAR, synthesis of tamoxifen. Aromatase inhibitors: steroidal e non steroidal derivatives, structures and SAR.

Progestins: structures, SAR, semisynthetic derivatives. Mifepristone. Oral contraceptives. Synthesis of norgestrel.

Androgens and anabolic steroids: structures, SAR.

Androgen receptor modulators: receptor blocking agents: cyproterone, flutamide. Androgen biosynthesis inhibitors: liarozole and finasteride.

Corticosteroids: mineralcorticoids, glucocorticoids, general aspects, SAR.


Readings/Bibliography

A. GASCO, F. GUALTIERI, C. MELCHIORRE, Chimica Farmaceutica, CEA, Milano, 2019

G.L. PATRICK, Chimica Farmaceutica, III Edizione italiana, EdiSES, Napoli, 2015.

J. M. BEALE, J. H. BLOCK, Wilson & Gisvold - Chimica farmaceutica, I Edizione italiana, CEA, Milano, 2014.

D.A. WILLIAMS, T.L. LEMKE, Foye's Principi di Chimica Farmaceutica, VI Edizione italiana, Piccin, Padova, 2014.

Slides and notes from the lessons

Teaching methods

The lectures will be in Italian.

Assessment methods

Modules 1 and 3 will be taken together.

The exam will consist of two portions: written and oral. The written part should be planned to immediately precede the oral exam and is focused on two syntheses among those listed in the program. The oral examination is a discussion aimed at ascertaining students' understanding of the subjects presented during lectures.

Regarding module 1, students can partecipate to an optional in itinere written test concerning the cholinergic system (excepting anticholinesterases)

Module 2

The exam will be taken in the same day of the other modules and will consist in an oral discussion aimed at assessing students' understanding of the subjects presented during lectures, involving the comment of a synthesis among those developed during lectures.

The final grade will be the weighted average of the marks obtained in the individual modules and will follow the Italian grading system. The passing mark is 18/30 and the top mark is 30/30.

Teaching tools

Power Point presentation.

Office hours

See the website of Alessandra Bisi

See the website of Alberto Leoni

See the website of Maria Laura Bolognesi