11777 - Medicinal and Toxicological Chemistry 2

Course contents

Module #1:

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), general synthesis of imidazoline, and 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, 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 ofranitidine; SAR of guanidinothiazole derivatives and piperidinomethylphenoxy derivatives. SAR of diarylic compounds

Antisecretory agents: omeprazole, SAR and mode of action.

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.

Module #2:

Drugs used in heart failure

Therapeutic approaches

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, nitrendipine, nisoldipine, nimodipine, amlodipine, nicardipine, felodipine, lacidipine, isradipine, lercandipine, manidipine, nivaldipine, palonidipine, azelnidipine.

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-generation statins: mevastatin, lovastatin, pravastatin

Second-generation statins: simvastatin

Third-generation statins: fluvastatin

Fourth-generation statins: cerivastatin, atorvastatin.

Fifth generation statins: rosuvastatin.

Readings/Bibliography

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

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

D. LEDNICER, L.A. MITSCHER, The Organic Chemistry of Drug Synthesis, voll. 1-6, John Wiley & Sons, New York, 1977, 1980, 1984, 1990, 1995, 1999.

C. Melchiorre, A. Minarini, M. Recanatini, V. Tumiatti, M.L. Bolognesi - I recettori colinergici - CLUEB, Bologna, 1997.

Slides and notes from the lessons.

Teaching methods

The lectures will be in Italian.

Assessment methods

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 final examination is an oral discussion that aim to ascertain students' understanding of the subjects presented during lectures. The final note will follow the Italian grading system. The passing mark is 18/30 and the top mark is 30/30. Eventual in itinere tests will be communicated during the opening lessons.

Teaching tools

Video projector, PC.

Office hours

See the website of Maria Laura Bolognesi

See the website of Alberto Leoni