11777 - Medicinal and Toxicological Chemistry 2

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 therapeutic use and chemical-toxicological aspects of drugs.

Course contents

GENERAL PART

Receptors, drug-receptor complex, receptor activation. 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. Selective antagonists for receptor subtypes: SAR.

Nicotinic agonists: SAR of nicotine and related compounds.

Nicotinic antagonists. Ganglionic blocking agents: mode of action, SAR. Neuromuscular blocking agents: SAR.

Cholinesterase inhibitors: mechanism of acetylcholine hydrolysis. Carbamates and reversibile cholinesterase inhibitors (Physostigmine, tacrine, donepezil), SAR. Multitarget approach to Alzheimer's Disease. Irreversible inhibitors, antidotes.

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.

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

Beta-adrenergic agonists. Discovery, development, SAR.

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, ethanolaminic derivatives, SAR, propilaminic derivatives, SAR. Second and third-generation antihistamines.

Histamine release inhibitors: sodium cromoglycate, structure, SAR.

Histamine receptor H2 antagonists: Imidazole derivatives, dimethylaminomethylfuranic derivatives, guanidinothiazole derivatives and piperidinomethylphenoxy derivatives. SAR.

Antisecretory agents: omeprazole, SAR and mode of action.

Cardiovascular drugs:

Drugs used in heart failure: cardioactive (digital) glycosides: chemistry of cardioactive glycosides. Derivatives of the digital. Strophan derivatives. Derivatives of the scilla. Mechanism of action of cardioactive glycosides.

The superfamily of phosphodiesterases. Pyrimidinone inhibitors (Amrinone, Milrinone). Non-pyrimidinone inhibitors.

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

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. Angiotensin II receptor blockers: development of losartan and derivatives.

Diuretics

Osmotic diuretics, sulfonamide diuretics, carbonic anhydrase inhibitors, xanthine diuretics. Thiazide diuretics: SAR, structures. Derivatives of sulfamoylbenzoic acid: examples, SAR. Unsaturated alpha-beta carbonyl derivatives: SAR. Potassium-sparing diuretics: antialdosterones: SAR, ENaC blockers: amiloride, triamterene, SAR.

Steroid Hormones: Structure, biosynthesis, steroid receptors. Drugs modulating cholesterol biosynthesis: statins.

Estrogens: structures, SAR, natural and synthetic estrogens.

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

Progestins: structures, SAR, semisynthetic derivatives. Mifepristone. Oral contraceptives.

Androgens and anabolic steroids: structures, SAR.

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

Biologic drugs: Application of innovative biotechnologies to the pharmaceutical industry: chemical synthetic strategies for antisense oligonucleotides and proteins.

EXERCISE ACTIVITIES

Target-based e ligand-based strategies in drug design.

Presentation of case histories

 

Readings/Bibliography

Class attendance is mandatory and the related power point presentations are part of the teaching material.

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

Teaching methods

The lectures will be in Italian.

Assessment methods

The oral examination is a discussion aimed at ascertaining students' understanding of the subjects presented during lectures.

Students can divide the exam into two parts, one concerning the autonomic nervous system and histaminergic drugs (including antisecretors) and the other concerning the rest of the programme, to be taken over the same year.

The passing mark is 18/30 and the top mark is 30/30. When taken in two parts, the final grade will be the average of the two individual grades.

Teaching tools

Power Point presentation.

Students can access the teaching material through the platform "Virtuale" of University of Bologna

Office hours

See the website of Alessandra Bisi