11777 - Medicinal and Toxicological Chemistry 2

Learning outcomes

The course of Medicinal and Toxicological Chemistry II is devoted to the study of the principal drug families which interact with the neurotransmitter receptors, the intracellular receptors, with enzymes and ion channels. During the course the aspects related to design, synthesis and  mechanism of action of drugs acting at the Autonomic Nervous System, antihistaminergic drugs, local anesthetics, diuretics, cardiovascular drugs,  and hormones will be considered, and detailed structure-activity relationships will be examined.

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, synthesis of metacoline.

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, carticaine/prilocaine.

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, synthesis.

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, 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.

 

Readings/Bibliography

MATERIAL GIVEN DURING CLASSES

C. MELCHIORRE, I Recettori dei Neurotrasmettitori, CLUEB

C. MELCHIORRE, I Recettori Colinergici, CLUEB

M. GIANNELLA, W. QUAGLIA, I Recettori Adrenergici, CLUEB

D.A. WILLIAMS, T.L. LEMKE, Foye's Principi di Chimica Farmaceutica, IV Edizione italiana, Piccin Padova, 2005

Teaching methods

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

Assessment methods

Verification of learning is carried out by means of an oral examination, which can only be sustained after the illustration of the synthesis of two drugs.

Teaching tools

Power Point presentation

Office hours

See the website of Alessandra Bisi