CHIMICA FARMACEUTICA AVANZATA - R.S.F.

The course aims to provide knowledge of the principal classes of drugs interacting with membrane receptors, intracellular receptors, enzymes and ionic channels. The course deals with the design, mode of action, structure-activity relationships (SARs), and metabolic fate of drugs. During the course a number of examples of industrial production of therapeutics are presented and discussed.

Having successfully completed the course, students will:

• have knowledge and understanding of name, structure, design, synthesis (only for selected compounds), physicochemical properties, structure of the biological target, mode of action, SARs and metabolic transformations of drugs belonging to classes object of the course;
• be able to apply knowledge and understanding in prediction of physicochemical properties of a structure, in discussion of their importance for the interaction with the target and for the expression of the biological properties, including metabolism (for drugs treated during the course and for analogues);
• be able in making proper judgements and comments about SARs, pharmacologic action, metabolism and eventual related toxicity of drugs belonging to classes object of the course;
• have skills in proper communication of issues presented during the course, answering to question with proper technical language;
• have learning skills in the inference of general rules (e. g.: structure-activity relationships in a drug class) from single cases, in searching and critically assessing information on drug structure and properties, how to manage and enlarge his/her own wealth of knowledge about medicinal chemistry.

The course is carried out through frontal lessons. During class lectures, all the subjects are presented in details. Students are asked to actively discuss about them and about a number of case studies.

Prerequisites are basic knowledges of Organic chemistry I, Biochemistry, Medicinal chemistry I (general section), Structure-activity analysis.

General section. Definition of drug. Receptors as targets of drug action. Receptors: definition, features, classification. Membrane receptors: G protein-coupled receptors, ionotropic receptors, tyrosine kinase receptors. Intracellular receptors. Definitions of agonist, partial agonist, antagonist, inverse agonist. Types of interactions and role of stereochemistry in the formation of the drug-receptor complex. Interactions between binging site and ligand. Case study 1: Interaction between Carazolol and beta₂-adrenergic receptor (D. M. Rosenbaum et al. Science, 318, 1266, 2007). Case study 2: Binding mechanism between Alprenolol and beta₂-adrenergic receptor (R. O. Dror et al., PNAS, 108, 13118, 2011). Enzymes as drug targets. Case study 3: Interaction between Atorvastatin and HMG-CoA reductase (E. S. Istvan, J Deisenhofer, Science, 292, 1160, 2001). Off targets: K⁺ hERG channels. Drug metabolism: role of the different P450 cytochrome isoforms.

Drugs acting on the cholinergic system. The parasympathetic nervous system. Structure, biosynthesis and metabolism of acetylcholine (ACh). Classification of cholinergic receptors, their tissue distribution and mechanism of signal transduction. Interaction between ACh and receptor binding site. Case 4 Study: Structure of the M₂ muscarinic receptor bound to an antagonist (K. Haga et al., Nature, 482, 547, 2012). Acetylcholine: structure, conformations, SAR. Muscarinic agonists: Methacholine, Carbachol, Bethanechol, Pilocarpine, Arecoline, Oxotremorine. Muscarinic antagonists, Atropine and Scopolamine, SAR antagonists. Ipratropium bromide, Benztropine, Propanteline bromide, QNB, Trihexyphenidil, Pirenzepine, Solifenacin. Case study 5: Structure of the nicotinic a4b2 receptor (C. L. Morales-Perez et al., 538, 411, 2016). Nicotinic agonists: Nicotine, Epibatidine, Varenecline. Nicotinic antagonists: neuromuscular blockers. Decamethonium, Succinylcholine, Tubocurarine, Pancuronium, Vecuronium, Rocuronium, Atracurium, Cisacurium, Mivacurium. Acetylcholinesterase, active site and mechanism of hydrolysis. Reversible acetylcholinesterase inhibitors. Fisostigmine, Neostigmine, Pyridostigmine, Edrophonium. Tacrine, Rivastigmine, Donezepil, Galantamine. Donezepil metabolism. Organophosphorus compounds and irreversible inhibition of acetylcholinesterase. Echothiophate. Pralidoxime iodide.

Drugs acting on the adrenergic system. The sympathetic nervous system. Structure, biosynthesis and metabolism of Noradrenaline (NE). Classification of adrenergic receptors, their tissue distribution and mechanism of signal transduction. Interaction between NE and receptor binding site. Adrenergic agonists with phenylethylamine structure: selectivity of receptor action, SAR and therapeutic uses. Phenylephrine, Isoproterenol, Terbutaline, Dobutamine, Salbutamol, Arformeterol, Salmeterol, Indocaterol. Synthesis of Salbutamol. Alpha₁-adrenergic agonists with arylimidazolinic structure: Nafazolin, Xylometazoline, Oxymetazoline. Alpha₂-adrenergic agonists: Clonidine. Adrenergic antagonists: receptor selectivity, SAR and therapeutic uses. Alpha₁-adrenergic antagonists: Prazosin, Terazosin, Doxazosin, Tamsulosin, Silodosin. Alpha-beta adrenergic antagonists: Labetalol, Carvedilol. Beta-adrenergic antagonists, SAR. Propranolol, Pindolol, Timolol, Nadolol. Selective beta₁-adrenergic antagonists: Practolol, Acebutolol, Atenolol, Metoprolol, Betaxolol, Esmolol. Synthesis of aryloxypropanolamine derivatives. Other drugs that influence adrenergic transmission: alpha-methyltyrosine, alpha-methyldopa.

Drugs acting on histaminergic receptors. Antiallergic and antigastrolesive drugs. Allergies and their mediators, biosynthesis and metabolism of histamine, histamine tautomers, histamine methylated derivatives. Histaminergic receptors and their classification. Case study 6: Structure of the H₁ histaminergic receptor in complex with Doxepin (T. Shimamura et al., 475, 65, 2011). First generation H₁ antagonists: ethanolamine derivatives, ethylenediamine derivatives, propylamine derivatives, piperazine derivatives, tricyclic derivatives. Second generation H₁ antagonists: Cetirizine, Levocetirizine, Terfenadine, Fexofenadine, Loratidine, Desloratidine, Acrivastine. Synthesis of Fexofenadine.

Peptic ulcer, gastric acid secretion, role of Helicobacter pylori. Histamine and H₂ receptors. H₂ antagonists, Cimetidine discovery: 4-methylhistamine, N-guanylistamine, Burinamide, Metiamide, Cimetidine synthesis and SAR; Ranitidine, Famotidine, Nizatidine, Roxatidine.

Proton pump inhibitors: mechanism of action, metabolism and synthesis of Omeprazole; Pantoprazole, Lansoprazole, Rabeprazole, Esomeprazole, Dexlansoprazole.

Non-steroidal anti-inflammatory drugs (NSAID). Pro-inflammatory and pro-resolution mediators. Biosynthesis of prostanoids and leukotrienes. Structure of PGH₂ synthase (Cyclooxygenase, COX) and cyclooxygenase and peroxidase catalytic sites. Isoforms of PGH₂ synthase: COX₁ and COX₂ and differences in their catalytic sites. Mechanisms of inhibition of COX. NSAID toxicity and selectivity in COX inhibition. Structural classes of NSAIDs and main SARs for each class. Salicylates: Acetylsalicylic acid (ASA), Diflunisal. Mechanism of action and metabolism of ASA. Synthesis of ASA. Aryl/heteroarylacetic acids: Indomethacin, Sulindac, Tolmetin, Zomepirac, Ketorolac, Etodolac, Diclofenac. Aryl/heteroarylpropionic acids: Ibuprofen, chiral center configuration and metabolism, Flurbiprofen, Ketoprofen, Naproxen, Nabumetone and its metabolic activation. Synthesis of Ibuprofen. Anthranilic acids: Mefenamic Acid, Flufenamic Acid, Meclofenamic Acid. Nimesulide. Oxicams: Piroxicam, Isoxicam, Tenoxicam, Lornoxicam Meloxicam, Sudoxicam. Metabolism of Meloxicam and Sudoxicam. Paracetamol: mechanism of action and metabolism. COXib: general structure and mechanism of action. Celecoxib, Etoricoxib, Rofecoxib, Valdecoxib, Lumiracoxib.

Drugs for Parkinson's therapy. General information on Parkinson's disease (PD) and on the involved neuronal circuits. Biosynthesis and catabolism of Dopamine. Classes of drugs in therapeutic use for PD. Levodopa and Melevodopa. Peripheral inhibitors of DOPA decarboxylase: Carbidopa and Benserazide. COMT inhibitors: Entacapone and Tolcapone. Irreversible MAO-B inhibitors: Selegiline, Rasagiline and the importance of the N-propargylic portion. Dopaminergic agonists: semisynthetic derivatives of ergot alkaloids, Bromicriptine, Pergolide, Cabergoline. Apomorphine, Ripinirole and Rotigotine. Cholinergic antagonists: Benztropine Trihexyphenidyl, Procyclidine.

Anxiolytic drugs. GABAergic receptor system, biosynthesis and catabolism of GABA. GABA_A receptor: structure and binding sites of GABA, Benzodiazepines (BDZ), Barbiturates.
Benzodiazepines: discovery of Chlordiazepoxide and Diazepam. Synthesis of Chlordiazepoxide. BDZ SAR, pharmacological actions and BDZ classification based on duration of action. Triazolam, Alprazolam, Lorazepam, Oxazepam, Potassium clorazepate, Diazepam, Nitrazepam. Antagonists for the BDZ site: Flumazenil. BDZ metabolism. Synthesis of Diazepam and Triazolam.
Zeta drugs: Zopiclone, Zolpidem, Zaleplon.

Antipsychotic drugs. General information on psychotic disorders. Symptomatology and pato-physiological hypothesis (dopaminergic, serotoninergic, glutamatergic) of schizophrenia. Classification of antipsychotic drugs, structure and SAR of the main chemical classes. Typical or first generation antipsychotics. Phenothiazine derivatives: Discovery of Chlorpromazine, Trifluoperazine, Perphenazine, Fluphenazine. Structural modifications and metabolism. Long-Acting-Injectable-Antipsychotics (LAIAs): Perphenazine enanthate, Fluphenazine decanoate. Thioxanthene derivatives: structure, geometric isomerism, SAR. Chlorprothixene, Thiothixene. Butyrophenone derivatives: structure, SAR. Haloperidol, Droperidol, Pimozide. Benzamide derivatives: discovery of Sulpiride starting from Metoclopramide, Amisulpiride. Atypical or second-generation antipsychotic drugs: mechanism of action, advantages over the typical antipsychotics, side effects. Clozapine, Olanzapine, Quetiapine, Risperidone, Paliperidone, Ziprasidone, Aripiprazole. Metabolism of Olanzapine.

Antidepressant drugs. General information on depression, symptomatology and pato-physiological hypotheses. Main classes of antidepressant drugs in therapeutic use. Monoamine oxidase inhibitors (IMAO): Phenelzine, Tranylcypromine, Moclobemide. Tricyclic antidepressants (TCA): Structure, conformation, mechanism of action, SAR. Imipramine, Desimipramine, Clomipramine, Amitriptyline, Nortriptyline, Dothiepin. Selective serotonin reuptake inhibitors (SSRIs): Fluoxetine and its metabolism, Sertraline, Paroxetine, Fluvoxamine, Citalopram, Escitalopram. Structural features common to SSRIs. Synthesis of Fluoxetine. Dual inhibitors of serotonin and norepinephrine reuptake (SNRI): Venlafaxine, Duloxetine, metabolism of Duloxetine. Norepinephrine reuptake inhibitors (NARI): Reboxetine, Bupropion, Bupropion metabolism. Alpha₂-AR receptor antagonists: Mirtazapine. Trazodone.

Opioid analgesics. Opium and its alkaloids, historical notes. Morphine, structure, conformation and configuration of chiral centers. Codeine, metabolism of Morphine and Codeine. Structural modifications on Morphine: Normorphine, Diacetylmorphine, 6-Acetylmorphine, Oxymorphine, Hydrocodone, Oxycodone; influence on the pharmacological activity of the substituent on the piperidine nitrogen atom: N-Phenethylmorphine, Nalorphin, Naloxone and Naltrexone. SAR for multicyclic opioids (4,5-epoxymorphinanes). General information on opioid receptors, their classification and localization. Endogenous opioid peptides: Enkephalins, Endorphins, Dinorphins. Structure of Met-enkephalin and Leu-enkephalin. Nociceptin and Endomorphins. Selectivity of opioid peptides for the different receptor subclasses. Message-Address Concept. Case study 7: Structure of the opioid receptor MOP in complex with a morphinane antagonist (A. Manglik et al., Nature, 485, 321, 2012). Stiffening of the morphine structure: Orvinols. Etorphine, Diprenorphine, Buprenorphine. Synthesis of the orvinol derivatives from Thebaine. Simplification of the morphine structure. Morphine derivatives: Levorfanol, Levallorfane, Dextromethorphan as antitussive agent. Benzomorphane derivatives: Metazocine, Phenazocine, Pentazocine. 4-Phenylpiperidine derivatives: Meperidine, Ketobemidone, SAR. 4-Anilinopiperidine derivatives: Fentanyl, Sufentanyl, Alfentanyl, Remifentanyl. Diphenylpropylamine derivatives: Methadone, Methadone metabolism. Opioids with a dual mode of action: Tramadol, Tapentadol. Opioids as antidiarrheal: Loperamide, Diphenoxylate. Naltrindole and development of bivalent ligands for opioid receptors: MDAN-21.

Antihypertensive drugs. Physiopathological aspects and pharmacological treatment of hypertension. Drugs active on the renin-angiotensin system. Angiotensin-converting enzyme inhibitors (ACE inhibitors): general structure, SAR, therapeutic indications. Captopril, Enalapril, Lisinopril, Fosinopril, Ramipril, Delapril, Zofenopril, Quinapril, Benazepril. Synthesis of Enalapril. Angiotensin II receptor antagonists: general structure, SAR, therapeutic indications. Development of Losartan, Valsartan, Irbesartan, Candersartan, Telmisartan, Olmesartan. Renin inhibitors: Aliskiren.
Structural organization and classification of calcium channels. Calcium antagonists: Diltiazem, Verapamil; Dihydropyridines: general structure, SAR, therapeutic indications. Nifedipine, Felodipine, Isradipine, Nitrendipine, Amlodipine, Nicardipine, Lacidipine, Lercanidipine, Manidipine, Nisoldipine. Synthesis of Nifedipine.
Beta-blockers and alpha₁-antagonists: general structure, SAR, therapeutic indications (see chapter: Drugs acting on the adrenergic system).
Endothelin receptor antagonists: Bosentan, Ambrisentan.

1. G.L. PATRICK, Chimica Farmaceutica, III Edizione italiana, EdiSES, Napoli, 2015
2. T.L. LEMKE et al., Foye's L'essenziale, Principi di Chimica Farmaceutica, I Edizione italiana, Piccin, Padova, 2017.
3. A. GASCO, F. GUALTIERI, C. MELCHIORRE, Chimica Farmaceutica, CEA, Milano, 2015
4. J. M. BEALE, J. H. BLOCK, Wilson & Gisvold - Chimica farmaceutica, I Edizione italiana, CEA, Milano, 2014.
5. D.A. WILLIAMS, T.L. LEMKE, Foye's Principi di Chimica Farmaceutica, VI Edizione italiana, Piccin, Padova, 2014.
6. Slides presented during classes..