11777 - Medicinal and Toxicological Chemistry 2

Course contents

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.

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.

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.

Local anestetics: Discovery, development, mode of action. Cocaine: structure and SAR. Benzoic acid derivatives: SAR, general synthesis. Amide derivatives: SAR, synthesis of lidocaine, tetracaine.

Cardiovascular agents: Cardiac action potential, ion channels.

Inotropic drugs: Cardiac glycosides: Structure, SAR, receptor hypothesis, mode of action. Phosphodiesterase inhibitors. Development of sildenafil.

Antiarrhythmic drugs: classification, mode of action, structures. Calcium modulators, structures, SAR, synthesis of Nifedipine, Verapamil.

Drugs for the treatment of angina pectoris, classification, SAR.

Antihypertensive drugs: direct vasodilators, structures, general aspects. RAS inhibitors: general aspects, inhibitors of angiotensin converting enzyme, structures, SAR, synthesis of captopril and enalapril. Angiotensin II receptor blockers: development of losartan and derivatives; synthesis of losartan.

Diuretics: osmotic diuretics, solfonamide derivatives, carbonic anhydrase inhibitors, xanthine derivatives. Thiazide diuretics: SAR, General synthesis of thiazides. Sulfamoyl benzoic acid derivatives: structures, SAR, synthesis of furosemide. Synthesis, SAR and mode of action of ethacrynic acid. Aldosterone antagonists: SAR, synthesis of spironolactone. Various compounds: amiloride, triamterene, mode of action, SAR.

Readings/Bibliography

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.

G.L. PATRICK, Introduzione alla Chimica Farmaceutica, II Edizione italiana, EdiSES, Napoli, 2010.

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 comprising three questions 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