91039 - Medicinal and Toxicological Chemistry II

Learning outcomes

By the end of the course, the student should gain a good understanding of the structural and mechanistic aspects of the drug-target interaction, with particular focus on the main classes of drugs interacting with the receptors of autonomic nervous system neurotransmitters, the intracellular receptors, the enzymes and the ion channels. In particular, the student acquires the basic skills to understand the chemical synthesis, the structure-activity relationships, the mechanism of action and the chemical-toxicological aspects of the drug classes dealt during the course.

Course contents

GENERAL PART

Concept of receptor. Types and nature of receptors. The bonds of the drug-receptor complex. Receptor activation: receptor theories. Competitive and non-competitive antagonism. Reverse agonism. Classification, location, function, structure, active site, second messenger and events following activation of adrenergic, cholinergic, histaminergic receptors.

DESCRIPTIVE PART

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

Muscarinic agonists, muscarinic SAR.

Muscarinic antagonists: SAR atropine and analogues, synthetic derivatives. Therapeutic use, general ester synthesis. Selective antagonists for receptor subtypes: SAR, pyrenzepine synthesis, metoctramine.

Nicotinic agonists: SAR nicotine and analogues

Nicotinic antagonists. Ganglioplegics, examples, SAR, pempidine synthesis. Curars, examples, SAR, succinylcholine synthesis, pancuronium.

Anticolinesterases: Mechanism of acetylcholine hydrolysis. SAR carbamates and reversible inhibitors (physostigmine, tacrine, donepezil) examples, carbamate synthesis: neostigmine/edrophonium, tacrine synthesis, SAR irreversible inhibitors (organophosphorus).

Adrenergic system: Biosynthesis and metabolism of catecholamines. Adrenergic receptor subtypes. Adrenalin and noradrenalin SARs.

Alpha-adrenergic agonists. Phenylethylamines, imidazolines, SAR, examples. Nasal decongestants, Anorectics, Amphetamine and Ephedrine. SAR, synthesis of catecholic and related derivatives (adrenalin, ethylephrine), Clonidine synthesis.

Alpha-adrenergic antagonists. Indole alkaloids, ergot alkaloids, imidazoline derivatives, quinazoline derivatives (prazosin synthesis), benzodioxane derivatives, aloalkylamines, disulphide tetrammines: SAR

Beta-adrenergic agonists. Development, SAR, resoprenaline/terbutaline synthesis, salbutamol.

Beta-adrenergic antagonists. Development, SAR arylethanolamines and aryloxy propanolamines, stereochemical aspects, example structures.

Local anaesthetics: historical development; SAR cocaine. Benzoic acid derivatives: SAR, examples, general ester synthesis. Amide derivatives: SAR, examples, synthesis lidocaine, tetracaine. Various compounds, mechanism of action.

Diuretics: osmotic diuretics, sulfonamide diuretics, carbonic anhydrase inhibitors, thiazide diuretics: SAR, general thiazide synthesis. Sulfamoylbenzoic acid derivatives: examples, SAR, furosemide synthesis. Xanthine diuretics: structures. Unsaturated alpha-beta carbonyl derivatives: SAR, synthesis etacrynic acid. Anti-aldosteronic diuretics: SAR, spironolactone synthesis. Various diuretics: amiloride, triamterene: SAR.

Histamine and Antihistamines: Biosynthesis, metabolism and structural aspects histamine, SAR, histaminergic receptor subtypes, agonists.

H1 Antihistamines: Ethylenediamines derivatives, SAR, tripelenamine synthesis; Ethanolamine derivatives, SAR, diphenhydramine synthesis; Propylamine derivatives, SAR chlorphenamine synthesis.

Histamine release inhibitors: Sodium chromoglycate, SAR, therapeutic use

H2 antihistamines, imidazole derivatives: SAR, cimetidine synthesis; dimethylaminofuran derivatives: SAR, ranitidine synthesis; guanidinothiazole derivatives, piperidinomethylphenoxy derivatives: SAR Diaryl compounds: SAR.

Non-histamine antisecretors: omeprazole, SAR and mechanism of gastric acid pump inhibition.

Drugs active on the cardiovascular system: Cardiac action potential, ion channels.

Cardiac glucosides: Structure, SAR, receptor hypothesis, mechanism of action.

Antiarrhythmic drugs: classification, mechanism of action. Main exponents of each class. Calcium modulators, examples, SAR, synthesis Nifedipine, Verapamil.

Antianginal drugs, examples.

Antihypertensive drugs: direct vasodilators, examples, general characteristics. Inhibitors of the renin-angiotensin system: generalities, conversion enzyme inhibitors, examples, SAR, captopril and enalapril synthesis. Angiotensin II antagonists: discovery, development of losartan and the sartan class, structure, SAR

Steroid hormones: structure, biosynthesis, steroid receptors.

Estrogens: structure, SAR, natural and synthetic estrogens, diethylstilbestrol synthesis.

Antiestrogens: receptor antagonists, triphenylethylene derivatives, tamoxifen, raloxifene and analogues, SAR. Steroid and non-steroid aromatase inhibitors, examples and SAR.

Progestatives: structures, SAR, semisynthetic derivatives. Mifepristone

Androgens and anabolics: structures, SAR.

Antiandrogens: receptor antagonists: cyproterone, flutamide. Biosynthesis inhibitors: liarozole and finasteride.

Corticosteroids: mineralcorticoids, glucocorticoids, general aspects, SAR.

Readings/Bibliography

Foye's Principles of Medicinal Chemistry (English Edition)

Teaching methods

The course is taught in English and involves frontal theoretical activities. All examination topics will be covered

Assessment methods

The examination consists of an oral discussion, the aim of which is to test the acquisition of the knowledge set out in the course objectives. A written illustration of the chemical synthesis of two of the drugs covered during the course and specifically indicated in the syllabus will also be required, followed by two questions on more general topics, and will be deemed passed by the correct answer to the questions posed, with particular regard to the relationships between chemical structure and biological activity and drug-target interaction. It is therefore relevant that the candidate has acquired knowledge from previous years' courses, in particular organic chemistry and biochemistry.

Teaching tools

Video projector - PC system. The slides presented in class are made available to students at the University of Bologna via the IOL platform

Office hours

See the website of Andrea Milelli