Pharmacy

1. HORMONES (3 CFU) Introduction a- Thyroid hormones and thyreostatics. Thyreoglobulin, T3 e T4 biogenesis, SAR, binding mode. Drugs for hypothyroidism (natural and synthetic). Drugs for hyperithyroidism - thyreostatics (propylthiouracil, methimazole, thiamazole, carbimazole). b-Insulin structure, stability, manifacturing. Oral hypoglicaemic agents (Arylsulfonylureas: carbutamide, tolbutamide, phenbutamide, chlorpropamide, glyburide, glymepiride. Repaglinide. Biguanides: metformin, buformin, phenformin. Glitazons: troglitazone, rosiglitazone, pioglitazone). c-Steroid hormones and related drugs. Introduction: sterols, gonane. Nomenclature, stereochemistry. c1-Sex hormones. Struttures: androstane, estrane, pregnane. Men’s health. Androgens: testosterone (s), metabolism, esters, androsterone, dehydroepiandrosterone. Synthetic androgens: methyltestosterone (s). Anabolic agents: clostebol, stanozolol, nandrolone (SAR). Andropause. Replacement therapy. SARM: N-arylpropionammides, bicalutammide. Benign Prostatic Hyperplasia: 5-redutctase inhibitors: medrogesterone, finasteride, dutasteride. Mechanism of action. 1-adrenergic antagonists: doxazosin, terazosin, prazosin, alfuzosin, tamsulosin. Fitotherapy, Serenoa repens and further plants. Treatment of Prostatitis. Treatment of prostatic cancer (refer to Medicinal and Toxicological Chemistry I schedule). Erectile Dysfunction. Introduction, penile protheses, vacuum constriction devices. Intracavernosal injection therapy. Papaverina, Phentolamine, PGE1. PDE5 inhibitors, meccanism of action. Sildenafil (s), vardenafil, tadalafil. Women’s health. Progestins: progesterone (s), metabolism. Synthetic Progestins: progesterone derivatives, ethisterone (s), derivatives and SAR. Progestin Antagonists. RU-486, mifepristone. Estrogens: estrone (s), estradiol (s), estriol. Structures. SAR. Estrogen receptors. Binding mode. Estrone Esters (prodrugs). Enterohepatic recycling. Conjugated estrogens. Synthetic Estrogens: ethynylestradiol (s), mestranol (s), quinestrol (s). Estradiol metabolism. Nonsteroidal Estrogens: diethylstibestrol, hexestrol, dienestrol, chlorotrianisene, clomifene. Antiestrogen agents. Estrogen Receptor Modulators (SERM): tamoxifen, toremifene, nafoxidine, ospemifene, raloxifene, arzoxifene. Raloxifene binding mode and comparison with the estradiol. Inhibitors of estradiol bioshyntesis. Steroids. Azoles (anastrozole, letrozole). Oral Contraceptives: estrogen-progestin oral combination; long-acting contraceptives; progestin-only oral contraceptives; emergency contraception. Toxicity. Infertility. Menopause. Breast Cancer. (refer to Medicinal and Toxicological Chemistry I schedule). c2-Mineralcorticoids and glucocorticoids. Desoxicorticosterone, aldosterone, hydrocortisone, cortisone. Biogenesis. Metabolism. Anti-inflammatory steroids: SAR. Prednisone, prednisolone, fludrocortisone, betametazone. d-Provitamin D: ergosterin, 7-dehydrocolesterol and transformation in D2 e D3 vitamins. 2. NERVOUS SYSTEM AGENTS 2a. Central Nervous System (3 CFU) A. Non-selective Depressants. a- General Anaesthesia. Introduction. SAR, activity, metabolism, administration route and toxicity. Inhalational anaesthetics: nitrogen protoxide, diethyl ether, chloroform, halogenated compounds, halothane (s, metabolism), enflurane, isoflurane, desflurane, sevoflurane. SAR. Metabolism, toxicity. CO2 absborbers and CO mproduction. Meccanism of action di azione: Mewyer-Overton theory, other mechanisms. Injection anaesthetics: introduction and meccanism of action, propofol and its metabolism, etomidate and its metabolism, ketamine and its metabolism, barbiturates, benzodiazepines, narcotic analgesics analgesic narcotics. b-Hypnotic and sedative agents. Introduction. Alcohols and carbammates: mefenesina, meprobamate. Barbiturates: barbital, phenobarbital (s), SAR, metabolism, toxicity. Isosteric analogs: glutetimide, talidomid. Benzodiazepines. Refer to ansiolitic agents. c- Narcotic Analgesics. Introduction. Syntheses, SAR, activity, metabolism, administration routes and toxicity. Enkephalins, endorphins. Morphine, codeine, thebaine, heroin. Hydromorphone, oxymorphone, Agonist and antagonist agents: nalorphine, naloxone. Molecular simplification: levorphanol, butorphanol, phenazocine (s), pentazocine, meperidine (s), methadone (s). Molecular complication: Etorphine (s) buprenorphine. Opioid receptor: models. Binding modes. Krokodil: history, industrial manufacturing and “in house” preparation. d- Non Narcotic Analgesics (analgesic-antipyretic-antiinflammatory agents). Introduction. Inflammation, autacoids, PG, arachidonic acid cascade. Use of AAA agents. Chemical classification. Benzoic acids: Aspirin (s) meccanism of action, diflunisal, fenamates (s); arylacetic acids: indomethacin (s), binding mode, active conformation; sulindac (s), SAR, binding mode, metabolism; tolmetin (s); arylpropionic acids, general structure, SAR, ibuprofen, ketoprofen (s), naproxen. Pyrazolone derivatives: struttures and metabolism, aminophenazone, metamizole (s). Pyrazolidinedione derivatives: phenylbutazone, metabolism, SAR and analogs. Oxicams: pyroxycam, SAR and analogs. p-Aminophenol derivatives: paracetamole, phenacetin, acetanilide, metabolism. COX-2 Selective Inhibitors. COX-1, COX-2 and their active sites. Binding modes, selective (celecoxib and other coxibs) and non-selective agents (diflunisal, indomethacin). Sulides (nimesulide and analogs). "Tricyclic" inhibitors, celecoxib, rofecoxib. B. Selective C.N.S. Depressing Agents a-Antiparkinson Drugs. Introduction. Anticholinergic agents. Amantadine. Dopamine Agonists. Direct agonists. Apomorphine. Bromocriptine. Carbidopa. DOPA decarboxylase inhibitors. b-Anticonvulsant Agents. Introduction. Barbiturates (Phenobarbital, mefobarbital, etobarbital, metabolism), primidons (metabolism), hydantoins, succinimides (carbamazepine, etosuccinimide), acylureas, SAR. Diltiazem, oxazolidinediones (trimetadione, metabolism), valproic acid, carbonic anhydrase inhibitors (acetazolamide). c-Neuroleptic agents. Introduction. Chemical classes. Reserpine and derivatives. Tricyclic compounds: phenothiazine: chlorpromazine discovery (s), metabolism, superimposition with dopamine, triflupromazine, side chain modification: perazines, phenazines (s), piperacetazine, pecazine, thioridazine. Thioxantenes. Chlorprothixene, thiothixene, chlopenthixol. SAR. 6,7,6 Tricyclic composti: chlothiapine, loxapine, chlozapine. Fluorobutyrophenones: haloperidol (s), droperidol. Benzamides: sulpiride, remoxipride. Poldinger graph. Activities and side effects for each class. d-Ansiolitic Agents. Introduction. Benzodiazepines: chlordiazepoxide discovery (s), nomenclature, SAR, binding mode, metabolism, toxicity, general synthetic pathways, demoxepam, diazepam, nordiazepam, oxazepam (s), triazolam (s). Benzodiazepine receptor. Agonists, antagonists and reverse agonista, Ro 15-1788 DMCM (-carboline). Centrally acting muscle relaxant agents: meprobamate. C. C.N.S. Stimulants Antidepressants: a-Timoleptic agents Introduction. Structures. Imipramine (s), desipramine, chlomipramine, opipramolo, protriptilina, amitriptilina, nortriptilina, maprotilina, dimetacrina, butriptilina, dossepina, dibenzepina. SAR. b-Timeretici. Metabolismo della NA, farmaci anti-MAO: idrazidi; idrazine: fenelzina, feniprazina; ammine: tranylcypromine, propargylamines, pargyline, chlorgylina and deprenyl, meccanism of action. 2b. Drugs acting on Autonomic Nervous System (2 CFU) Introduction. Receptors. Pharmacological activities. Nomenclature. a- Adrenergic receptors ligands. Adrenergic agents: Direct simpaticomimetics: agonists: epinephrine, norepinephrine (biogenesis, metabolism), phenylephrine, metaraminol, synephrine, metoxamine; amphetamine, methamphetamine, MDMA, ephedrine. Selectivity: -agonists: isoprenaline, salbutamole, dobutamine, isoxisuprine. SAR. Activity – side effects on CNS and approaches to limit them. Non-phenethylamine adrenergics: naphazoline. General synthetic pathways. Drugs that interfere with the synthesis, metabolism, stockage and uptake of epinephrine and norepinephrine. Adrenergic Antagonists. Alpha-blockers: phenoxybenzamine, imidazolines (phentolamine and tolazoline), prazosin, Ergot alcaloids. Beta-blockersi: structural elements leading to beta-selectivity. Examples. See also drugs acting on cardiovascular system. b- Cholinergic receptor ligands. Cholinergic synapse. Biogenesis and metabolism of acetylcholine (acetylcholine esterase). Muscarinic and nicotinic receptors. Acetylcholine active conformazions on muscarinic and nicotinic receptors, respectively. Cholinergic agents. Direct acting cholinergic agents. Acetylcholine, methacholine, carbachol, bethanechol. Acetylcholine esterase, mechanism of hydrolysis. Metabolism and duration of action. SAR. Syntheses of acetylcholine and carbacholo. Indirect acting cholinergic agents. Reversibile, irreversibile and partially-reversibile acetylcholine esterase inhibitors. Edrofonium, neostigmine, pyridostigmine, physostigmine, organophosphoric derivatives. Acetylcholine esterase reactivators: pralidoxime. Cholinergic receptors blockers. Antimuscarinic agents. Chemical Classes. Belladonna Alcaloids. Adiphenine, piperidolate, mepenzolate. Binding mode. Neuromuscular blockers. Curares, tubocurarine. Depolarizing agents: decamethonium, sussamethonium. Miotropic spasmolytic agents: papaverine (s), ethaverine. Meccanism of action. 2c. Local Anaesthetics. (0,5 CFU) Introduction. Syntheses, SAR, pharmacological activity, metabolisms, nomenclature, administration route and toxicity. Cocaine (strutture, ecgonine), procaine (metabolism), tetracaine. Lidocaine (s), pyrrocaine, mepivacaine, bupivacaine. SAR, pKa. 3. HISTAMINE AND ANTIHISTAMINE AGENTS. (0,5 CFU) Introduction. Histamine: strutture, conformations, physical and chemical properties and biogenesis. Mepyramine and analogs, clemizole, antazoline, chlorphenamine, diphenhydramine, chlorcyclizine, phenothiazines: promethazine. SAR, pharmacological activity and toxicity. Binding mode of histamine to H1 receptor. Binding mode of histamine to H2 receptor and activation. H2 receptor antagonists, discovery of burimamide, thiaburimamide, cimetidine, ranitidine. 4. DRUGS ACTING ON CARDIOVASCULAR SYSTEM. (2 CFU) 3a. Analeptics. Introduction. Strychnine, pentamethylene tetrazole, xanthines: theophylline, caffeine. Meccanism of action. 3b. Antiarrhythmic agents. Properties and classification. Class 1. Procainamide, metabolism; lidocaine. Class 2. Beta-blockers. SAR. Class 3. amiodarone. Class 4: calcium antangonist. Verapamil, dihydropyridines, dilthiazem. 3c. Coronary dilatators. Introduction. Nitrites and nitrates. Betablockers. Calcium-antagonists: dihydropyridines: SAR, nifedipina, nitrendipine, metabolism. Verapamil, metabolism, related drugs; benzothiazepines: dilthiazem (s). Khelline analogs: methylchromone, amiodarone (s). Coenzymes and vitamins: carnitine. 3d. Cardiotonic Agents. Agonista of beta adrenergic receptor. Inhibitors of cAMP phosphodiesterase: amrinone (s), milrinone, SAR and binding mode. Drugs that increase the concentration of Ca++: levosimendan. Inhibitors of Na+/K+ ATPase: istarossime. Cardiotonic heterosides. Structures, isolation and purification. Aglycones and glycosides properties. Heterosides from digitalis purpurea and lanata. Heterosides from strofantus. Heterosides from scylla. Meccanism, binding mode, toxicity, uses. 3e. Hypolipidemic agents. Introduction. Fibrates: chlofibrate and analogs. Chlofibrate metabolism. Nicotinic acid. Dextrothyroxine. Pyridinol carbamate (s). Statins (HMG-CoA reductase inhibitors): lovastatin and congeners. Resins: cholestyramine. 3f. Antihypertensive agents. Alfa-blockersi: prazosin. Beta-blockers: SAR. Direct action dilatators: nitroprussiate, diazoxide, dihydralazine, minoxidil (s). Calcium antagonists. Central acting dilatators: clonidine and congenere, SAR, binding mode. Alfa-methyl DOPA (s). Reserpine, rescinamine and derivatives. ACE inhibitors: Drugs acting on sul renin-angiotensin system: captopril (s), enalapril (s), enaprilate. ACE model from Cushman and from Petrillo-Ondetti. SAR for ACE inhibitors. Captopril metabolism. Angiotensina II Receptor Antagonists: Saralasina, sartani: losartan (s). Renin Inhibitors: Aliskiren. 3g. Drugs for DE treatment. See above: Men’s health. 3h. Diuretic agents. Introduction. Arylsulfonamides: acetazolamide, SAR. Thiazides and dihydrothiazides, properties and SAR. Loop diuretics: etacrinic acid. Aldosterone blocking diuretics: canrenone, canrenoic acid, spironolattone. Vasopressin antagonists. Conivaptan. Tolvaptan.

Essential: for the right comprehension of the lessons of Drug Design, basics of Organic Chemistry, Biochemistry, Human Anatomy are necessary. Relevant: basics of Pathology, Pharmacology, Pharmacognosy, Toxicology. Useful: basics of Medicinal Chemistry general concepts, Drugs analysis are useful.

Gasco, Gualtieri, Melchiorre – Chimica Farmaceutica, SEA Editore

Attendance of the course is mandatory.

Monthly exame will be fixed (may and august excluded) in wich oral evaluation will be performed. The oral exame takes half an hour for each student. Following the theacher query, the student will show a drug covering every aspect. At the end of presentation the the teacher will ask critical questions and expand discussion on the therapeutic class of the cited drug asking connections with part of the remaining program. The procedure is repeatd 3 times covering the main therapeutic classes included in the program (hormeones, nervous system drugs, cardiovascular dugs). The objective is to attest the student knowledge about the drug discovery. The matter should be presented with speech suitable to a drug professionist. At the end ot the exame the teacher will ecvaluate: the knowledge of the matter, allover the program, the proper speech, the participation throughout the course, the thinking ability, the indipendency of the student to study on the textbook. To gain the minimum (18) the student is required to sufficently present the drug, to have a sufficient knowledge of the structure-activity relationships, the knowledge of the synthesis of the main compound of the therapeutic class, and to be able to describe the binding mode of the main compound with its target. To gain maximum (30/30 and laude) the student should prove to have aquired an excellent knowledge of all matter of the course, also being able to link all the matter in a logical and coherent way. The student must demonstrate also to take the matter properly and smothly moving in a drug discovery process. In summary, she/he must prove 100% to go further the knowledge of the basic concept showing an excellent profile.

Notes form lessons Parts form Foye – Principi di Chimica Farmaceutica, Piccin Editore