11777 - Medicinal and Toxicological Chemistry 2

Course contents

Module 1: general part, drugs interacting with autonomic nervous system, histaminergic receptors and cytoplasmic 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.

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

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.

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.

Module 2 Cardiovascular agents – Prof. Rita Morigi

Cardiac action potential, ion channels.

Cardiac glycosides: Structure, SAR, receptor hypothesis, mode of action.

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.

 

Readings/Bibliography

Material given during classess, also available on the Virtuale Platform.

For further information refer to the following books:

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

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

Teaching methods

During the lessons all the drug classes will be treated as reported in the course contents.

Assessment methods

The examination consists in an oral interview aimed at proving the acquisition of the information presented in the objectives of the course.

Module 1. First, the student should write down and comment two chemical synthesis of drugs among those specifically listed in the program. Then, two more general questions about related topics (with particular consideration for the relationships between chemical structure and biological activity and drug-target interactions) will follow. Therefore, it is of particular importance that the candidate has acquired knowledge from previous courses, especially organic chemistry and biochemistry. The minimum grade to pass the examination is 18/30

Module 2. The oral interview includes two or three questions, which aim to assess the level of knowledge of the fundamental aspects concerning the design, the mechanisms of action, and the SARs of the classes of drugs specifically indicated in the module program. It may also concern the chemical syntheses covered during the course. The minimum grade to pass the examination is 18/30.

The final grade of the entire course will be calculated as a weighted average of the grades reported in the individual modules.

Teaching tools

Power point presentation

Office hours

See the website of Alessandra Bisi

See the website of Rita Morigi