11777 - Medicinal and Toxicological Chemistry 2

Academic Year 2020/2021

  • Teaching Mode: Traditional lectures
  • Campus: Rimini
  • Corso: Single cycle degree programme (LMCU) in Pharmacy (cod. 9223)

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 general synthetic methods, the therapeutic use and chemical-toxicological aspects of drugs.


Course contents

GENERAL PART

Receptors, drug-receptor complex, receptor activation, principles of receptor theory. Competitive and non competitive antagonism. Classification, structure and function of adrenergic, cholinergic and histaminergic receptors.

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

Muscarinic agonists: SAR of muscarine.

Muscarinic antagonists: SAR of atropine and related derivatives. SAR of synthetic compounds. Mode of action, therapeutic use. 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, Amfetamine 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 Prazosine), benzodioxane derivatives, haloalkylamines, disulfur tetramines.

Beta-adrenergic agonists. Discovery, development, SAR, synthesis of resoprenaline/terbutaline, salbutamol.

Beta-adrenergic antagonists. Discovery, development, SAR arylethanolamines and aryloxypropanolamines,

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.

Histamine and antihistaminic: istamine: structure, biosynthesis and metabolism, SAR, istamine 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.

Istamine 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.

Cardiovascular agents: 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.

Steroid hormones: Structure, biosynthesis, steroid receptors.

Estrogens: structures, SAR, natural and synthetic estrogens, synthesis of diethylstilbestrol.

Estrogen receptor modulators: receptor antagonists, triphenylethylamine derivatives, tamoxifen, raloxifen and related compounds, SAR.

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.

Readings/Bibliography

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

For further information refer to the following books:

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

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

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.

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. The student should also write down and comment two chemical synthesis of drugs among those specifically listed in the program, and 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.

Teaching tools

Power Point presentation

Office hours

See the website of Alessandra Bisi

SDGs

Good health and well-being

This teaching activity contributes to the achievement of the Sustainable Development Goals of the UN 2030 Agenda.