CHIMICA FARMACEUTICA E TOSSICOLOGICA II

1. Knowledge and Understanding

The student will be able to describe and explain the fundamental concepts that characterize Medicinal and Toxicological Chemistry.

2. Applying Knowledge and Understanding

The student acquires the skills necessary to understand the properties of selected drug classes and how they interact with neurotransmitter receptors, intracellular receptors, enzymes, and ion channels, exploring their mechanisms of action, chemical-pharmaceutical and toxicological properties, and structure-activity relationships (SARs).

3. Making Judgments

The student develops critical thinking skills in evaluating a drug's properties in relation to its chemical structure.

4. Communication skills

Students will acquire the ability to communicate and convey what they have learned during the course using appropriate scientific language and to discuss the strategies adopted for drug design, synthesis, and development.

5. Learning skills

Students will develop the ability to independently locate bibliographical material and update their knowledge, including through the consultation of specialized databases, in order to delve deeper into the topics covered and develop an independent study method useful for completing their studies.

The course comprises a total of 68 hours, structured as 56 hours of lectures (8 CFU – direct instruction) and 12 hours of classroom exercises (1 CFU – interactive instruction). During lectures, students will be expected to participate actively in discussions on the topics covered, engaging in exercises and problem-based learning. Additionally, classroom exercises modeled on the actual exam format will be conducted throughout the course.

According to the RDA, art. 12 - University Education al Credits (CFU), the standard 25-hour workload of the student, corresponding to one credit, may include: a) 7 hours dedicated to lectures or equivalent teaching activities and the remainder to individual study; b) at least 12 hours and no more than 15 hours dedicated to classroom exercises or equivalent supervised activities (workshops) and the remainder to personal study and revision.

If teaching is taught in blended or distance learning mode, any necessary changes to what was previously stated may be introduced in order to comply with the planned program reported in the syllabus.

Prerequisites as per the study plan

A proper understanding of the topics covered in the course requires prior knowledge of General Chemistry (useful), Organic Chemistry (essential), Biological Chemistry, Anatomy, Physiology, Pathology, Pharmacology (important), and Pharmaceuticals I (essential).

Attendance is mandatory as per the Degree Program's academic regulations. Absences are permitted for no more than 30% of the total class hours, assessed in all formats (https://www.dsf.unict.it/it/corsi/lm-13/regolamento-didattico).

If the course is taught in a blended or distance learning format, any necessary changes to the previously stated curriculum may be made in order to comply with the planned program and the syllabus.

CHOLINERGIC AGENTS

Central and peripheral nervous system. Cholinergic system: cholinergic signal transmission; acetylcholine (ACh): biosynthesis, metabolism, cholinergic receptors (types, localization, and function). ACh: structure and conformations, rigid analogues, structure-activity relationships (SAR), interactions of ACh with its receptors. ACh analogues: methacholine, carbachol, bethanechol. Muscarinic agonists (clinical uses): muscarine, pilocarpine. Nicotinic agonists: nicotine, methacholine, varenicline. Muscarinic antagonists (clinical uses): atropine, hyoscine, scopolamine. Atropine SAR and analogues: amprotropine, ipratropium, propantheline, benztropine, pirenzepine. Nicotinic antagonists (clinical uses): tubocurarine, decamethonium, succinylcholine, pancuronium, atracurium, mivacurium.

Anticholinesterases: mechanism of enzymatic hydrolysis of ACh. Organization and catalytic site. Carbamates (reversible inhibitors): physostigmine and analogues (miotine, neostigmine, pyridostigmine). Organophosphorus compounds (irreversible inhibitors): dyflos, sarin. Insecticides: malathion. Antidotes: pralidoxime, pro-2-PAM. Smart drugs: tacrine, donepezil.

ADRENERGIC AGENTS

Central and peripheral nervous system. Adrenergic system: adrenergic signal transmission; noradrenaline (NA): biosynthesis and metabolism of catecholamines. Potential pharmacological targets in adrenergic transmission. Adrenergic receptors: types, distribution, function, and classification. The adrenergic receptor binding site. SAR of catecholamines/phenylethylamines regarding interaction with α and β receptors, agonism, and antagonism. α-Agonists (clinical uses): ephedrine, pseudoephedrine, phenylephrine, naphazoline, oxymetazoline, xylometazoline, clonidine. β-Agonists (clinical uses): isoprenaline, isoetharine, soterenol, salbutamol (synthesis included), salmefamol, salmeterol. α-Antagonists (clinical uses): phenoxybenzamine; prazosin, terazosin, doxazosin, alfuzosin, mirtazapine. β-Antagonists (clinical uses): aryloxypropanolamines (synthesis and stereochemistry); first-generation β-blockers: pronethalol, propranolol, nadolol, pindolol, timolol. Second-generation β-blockers: practolol, acebutolol, atenolol, metoprolol, betaxolol, esmolol. Drugs affecting adrenergic transmission: α-methyltyrosine, α-methyldopa, bretylium, imipramine, reboxetine, bupropion, cocaine, amphetamines, tyramine, ephedrine, phentermine, tranylcypromine.

ANTI-ALLERGY DRUGS: H₁-ANTIHISTAMINIC

Allergies and their mediators. Histamine and its forms. Predominant species and tautomers at physiological pH. Chemical properties. Histamine biosynthesis and metabolism. Histamine receptors: types, localization, function, and classification. Interactions of histamine and antihistamines with their receptors. Agonists: betahistine. First-generation antagonists: piperoxan, phenbenzamine. Ethylenediamine derivatives: mepyramine, antazoline. Ethanolamine derivatives: diphenhydramine, dimenhydrinate, doxylamine, clemastine. Propylamine derivatives: chlorpheniramine, (dexchlorpheniramine); synthesis of propylamine derivatives. Propenylamine derivatives: Z and E configuration, triprolidine. Piperazine derivatives: cyclizine, hydroxyzine. Tricyclic derivatives: promethazine, cyproheptadine, azatadine, doxepin. Second-generation antagonists: levocetirizine and cetirizine, terfenadine and fexofenadine, loratadine, desloratadine, acrivastine.

Histamine release inhibitors: sodium cromoglicate. Phosphodiesterase inhibitors: theophylline. Leukotriene inhibitors: montelukast.

H₂-ANTIHISTAMINIC.

Peptic ulcer, gastric acid secretion. Histamine and its forms. Agonists: 4(5)-methylhistamine. Antagonist development: lead development. N-α-guanylhistamine, guanidine derivatives, isothiourea derivatives, (SKF91581), burimamide, thiaburimamide, metiamide. H₂-selective antagonists: cimetidine (synthesis), ranitidine (SAR), famotidine, nizatidine. General SAR. Pharmacophore structure. Physicochemical properties.

PROTON PUMP INHIBITORS (PPIs)

Parietal cells and hydrochloric acid production. Omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole. Omeprazole: discovery, mechanism of action, metabolism, synthesis. Physicochemical properties and SAR. Helicobacter pylori and therapy. Other anti-acid drugs: Sucralfate, bismuth salicylate, pirenzepine.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)

Inflammation; pro-inflammatory and pro-resolving mediators. Prostanoids and leukotrienes; biosynthesis of prostanoids and leukotrienes. Cyclooxygenase (COX) and its catalytic sites (cyclooxygenase and peroxidase sites). COX-1 and COX-2 isoforms and differences in their catalytic sites. Mechanisms of COX inhibition. NSAID toxicity and selectivity of 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. Pyrazolones: Phenylbutazone, Aminopyrine, Metamizole. Aryl/heteroaryl acetic acids: Indomethacin, Sulindac, Tolmetin, Ketorolac, Diclofenac. Aryl/heteroaryl propionic acids: Ibuprofen (configuration at the chiral center 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, Meloxicam, Sudoxicam. Metabolism of Meloxicam and Sudoxicam. Paracetamol: mechanism of action, metabolism, and toxicity. COXibs: general structure and mechanism of action; Celecoxib, Etoricoxib, Rofecoxib, Valdecoxib, Lumiracoxib. Leukotriene synthesis inhibitors and receptor antagonists: Zileuton, Montelukast.

Antirheumatic drugs. Gold compounds: clinical applications and side effects.

Drugs for the treatment of gout: allopurinol, probenecid. Drugs for the treatment of multiple sclerosis: fingolimod, dimethyl fumarate, and dalfampridine.

ANTIHYPERTENSIVE DRUGS

Pathophysiological aspects and pharmacological treatment of hypertension. Drugs acting on the renin-angiotensin system. Angiotensin-converting enzyme (ACE) inhibitors: general structure, SAR, therapeutic indications. Captopril (discovery of), Enalapril (Enalaprilat), Lisinopril, Benazepril. Angiotensin II receptor antagonists (sartans): general structure, SAR, therapeutic indications. Development of Losartan. Candesartan, Olmesartan. Renin inhibitors: Aliskiren.

Structural organization and classification of calcium channels. Calcium channel blockers: Diltiazem, Verapamil, Dihydropyridines (DHPs): general structure, SAR, therapeutic indications. Nifedipine, Nitrendipine, Amlodipine, Lercanidipine. Synthesis of symmetric (Nifedipine) and asymmetric (Nitrendipine) DHPs.

Agents acting on the adrenergic system (see also the topic of adrenergics). Peripherally acting adrenergic agents: Beta-blockers—general structure, therapeutic indications (propranolol, pindolol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol, celiprolol, carvedilol); alpha-1 antagonists (prazosin, terazosin, doxazosin). Centrally acting adrenergic agents (clonidine, moxonidine, methyldopa).

DRUGS FOR THE TREATMENT OF PARKINSON'S DISEASE.

Overview of Parkinson's disease (PD) and the neuronal circuits involved. Dopamine biosynthesis, catabolism, and receptors. Classes of drugs used therapeutically for PD. Dopamine biosynthesis precursors: Levodopa and Melevodopa. Peripheral DOPA decarboxylase inhibitors: Carbidopa and Benserazide. Amantadine. COMT inhibitors: Entacapone and Tolcapone. Irreversible MAO-B inhibitors: Selegiline and Rasagiline. Dopamine agonists: semi-synthetic ergot alkaloid derivatives—Bromocriptine, Pergolide, Cabergoline (lysergic acid derivatives); Apomorphine, Ropinirole, and Rotigotine. Cholinergic antagonists: Benztropine, Trihexyphenidyl, Procyclidine.

ANTIPSYCHOTIC DRUGS

Overview of psychotic disorders. Symptomatology and pathophysiological hypotheses (dopaminergic, serotonergic, glutamatergic) of schizophrenia. Classification of antipsychotic drugs; main chemical classes. Typical or first-generation antipsychotics. Phenothiazine derivatives: Chlorpromazine and its discovery. Trifluoperazine, Perphenazine, Fluphenazine. Phenothiazine SAR. Thioxanthene derivatives: structure, geometric isomerism, SAR. Chlorprothixene, Thiothixene. Structural overlap of phenothiazines and thioxanthenes with dopamine. Metabolism of phenothiazines and thioxanthenes. Long-Acting Injectable Antipsychotics (LAIAs): Perphenazine enanthate, Fluphenazine decanoate, Thioxanthene decanoate. Butyrophenone derivatives: Structure, SAR, and metabolism. Haloperidol, Droperidol, Pimozide. Benzamide derivatives: discovery of Sulpiride starting from Metoclopramide; Amisulpride. Atypical or second-generation antipsychotic drugs: mechanism of action, advantages over typical antipsychotics regarding side effects. Diarylazepines: Clozapine, Olanzapine, Quetiapine (metabolism of diarylazepines). Benzisoxazoles and benzothiazoles: Risperidone, Paliperidone, Ziprasidone, Aripiprazole (metabolism). Synthesis of clozapine.

ANTIDEPRESSANT DRUGS

Overview of depression, symptomatology, and pathophysiological hypotheses. Serotonin biosynthesis, catabolism, and receptors. Main classes of antidepressant drugs in therapeutic use. Monoamine oxidase inhibitors (MAOIs): irreversible (Phenelzine, Tranylcypromine) and reversible (Moclobemide). Tricyclic antidepressants (TCAs): structure, conformation, mechanism of action, and SAR. Imipramine, Desipramine, Clomipramine, Amitriptyline, Dotiepin. Selective serotonin reuptake inhibitors (SSRIs): Fluoxetine, Sertraline, Paroxetine, Fluvoxamine, Citalopram, Escitalopram. Common structural motifs of SSRIs. Synthesis of Fluoxetine. Serotonin-norepinephrine reuptake inhibitors (SNRIs): Venlafaxine, Duloxetine. Norepinephrine reuptake inhibitors (NARIs): Reboxetine. Norepinephrine-dopamine reuptake inhibitors (NDRIs): Bupropion; Bupropion metabolism. α₂-AR antagonists: Mirtazapine. 5-HT₂ antagonists/5-HT reuptake inhibitors: Trazodone. Antidepressant/mood-stabilizing drugs: Lithium carbonate, Valproic acid, Carbamazepine.

ANXIOLYTIC/SEDATIVE/HYPNOTIC DRUGS

Definition of anxiolytic-sedative-hypnotic drugs. ANXIOLYTICS: Overview of anxiety. GABAergic receptor system; GABA biosynthesis and catabolism. GABAA receptor: structure and binding sites for GABA, benzodiazepines (BDZs), and barbiturates. Benzodiazepines: discovery of Chlordiazepoxide. Synthesis of Diazepam. SAR of benzodiazepines (BZDs), pharmacological actions (therapeutic effects and side effects), and classification of BZDs based on duration of action. Triazolam, Alprazolam, Lorazepam, Oxazepam, Clorazepate dipotassium, Diazepam, Nitrazepam, Flunitrazepam. BZD site antagonists: Flumazenil. BZD metabolism. Anxiolytics interacting with the serotonergic system: buspirone, SSRIs. "Z-drugs": Zopiclone, Zolpidem, Zaleplon.

SEDATIVE-HYPNOTICS: overview of the sleep-wake cycle. Melatonin biosynthesis. Barbiturates: mechanism of action, SAR, clinical applications, and side effects. Amobarbital, butabarbital, pentobarbital, phenobarbital, secobarbital, Thiobarbital. Metabolism of pentobarbital and phenobarbital. Non-benzodiazepine GABAA receptor agonists: zolpidem (SAR and metabolism), zopiclone (and its metabolism), zaleplon (and metabolism), clinical applications. Melatonin receptor agonists: (S)-Ramelteon, Tasimelteon; SAR, clinical applications, and (S)-Ramelteon metabolism. Histamine H₁ receptor antagonists: diphenhydramine, doxylamine; mechanism and side effects.

OPIOID ANALGESICS

Opium and its alkaloids; historical overview. Morphine: structure and properties, conformation and configuration of chiral centers. General aspects of opioid receptors: classification and localization. Endogenous opioid peptides: Enkephalins, Endorphins, Dynorphins. Structure of Met-enkephalin and Leu-enkephalin. Nociceptin and Endomorphins. Selectivity of opioid peptides for different receptor subclasses. Message-Address Concept – enkephalin binding theory. Morphine and the blood-brain barrier (BBB): Normorphine, diacetylmorphine, 6-acetylmorphine. Structural modifications of morphine, key functional groups, SAR, pharmacophore, interactions with the μ-receptor. Codeine; metabolism of morphine and codeine. Structural modifications of morphine: Extension—oxymorphone, hydrocodone, oxycodone; influence of the substituent on the piperidine nitrogen atom on pharmacological activity—N-phenethylmorphine, nalorphine, naloxone, and naltrexone. Simplification, removal of ring D: Morphinan derivatives—levorphanol, levallorphan, dextromethorphan (as an antitussive). Removal of rings C and D: Benzomorphan derivatives—metazocine, phenazocine, pentazocine. Removal of rings B, C, and D: 4-Phenylpiperidine derivatives—meperidine, ketobemidone, SAR. 4-Anilinopiperidine derivatives—fentanyl (formulations, metabolism), sufentanil, alfentanil, remifentanil. Removal of rings B, C, D, and E: Diphenylpropylamine derivatives—methadone, methadone metabolism. Rigidification of the morphine structure: Orvinols—etorphine, diprenorphine, buprenorphine. Naltrindole and the development of bivalent ligands for opioid receptors: MDAN-21. Opioids as antidiarrheals: Loperamide, diphenoxylate. Dual-action opioids: Tramadol, tapentadol.

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. G. COSTANTINO, G. SBARDELLA, CHIMICA FARMACEUTICA, Edises Università, 2024

5. Lecture notes and slides

The assessment consists of a written exam (90 minutes) comprising multiple-choice and open-ended questions. Multiple-choice questions will be assigned a fixed score for a positive answer, zero for a non-positive answer, and a negative score for an incorrect answer. Open-ended questions will be assigned a variable score based on the level of detail provided by the answer.

The exam is designed to assess

• the student's knowledge of the basic concepts of Medicinal Chemistry and Toxicology (Descriptor 1);

• the fundamental aspects of design, molecular mechanisms of action, synthesis, and SARs of the drug classes covered during the course (Descriptor 2);

• the critical ability to evaluate the properties of a drug in relation to its chemical structure (Descriptor 3);

• the ability to communicate and convey what has been learned during the course through the correct and appropriate use of scientific language (Descriptor 4);

• the ability to independently integrate the information learned during the course (Descriptor 5).

Assessment Criteria

The final exam will be assessed based on indicators weighted equally and consistently with those described in the expected learning outcomes (Dublin Descriptors).

Therefore, the final grade takes into account the following factors:

Quality of knowledge, skills, and competencies possessed and/or demonstrated:

a) appropriateness, accuracy, and consistency of knowledge

b) appropriateness, accuracy, and consistency of skills

c) appropriateness, accuracy, and consistency of skills

Method of presentation:

a) Expressive ability

b) Appropriate use of subject-specific language;

c) Logical ability and consistency in connecting content;

d) Ability to connect different topics by identifying common ground and establishing a coherent overall design, i.e., by focusing on the structure, organization, and logical connections of the expository discourse;

e) Ability to summarize, including through the use of subject-specific symbolism and the graphical expression of notions and concepts, for example, in the form of formulas, diagrams, and equations.

Interpersonal Skills:

a) Willingness to exchange and interact with the instructor during the interview.

Personal Skills:

a) Critical thinking;

b) Self-assessment skills;

c) Problem-solving skills;

d) Decision-making skills.

 

Based on the above, the assessment may be:

Not sufficient or very insufficient (Exam failed, grade from 10 to 17):

The student does not possess the minimum required knowledge of the main content of the course. The ability to use specific language is very limited or nonexistent, and the student is unable to independently apply the acquired knowledge.

Sufficient (Grade 18-20):

The student demonstrates little acquired knowledge, a superficial level, and many gaps; he or she has a modest ability to integrate and critically analyze the situations presented and presents the topics sufficiently clearly, although his or her command of language is poorly developed.

Fair (Grade 21-23):

The student demonstrates a reasonable grasp of knowledge, with few gaps, but limited depth of understanding; expressive skills are more than sufficient to sustain a coherent discussion; acceptable command of scientific language; logical and coherent skills in connecting moderately complex topics; more than adequate ability to summarize and acceptable graphical expression.

Good (Grade 24-26)

The student demonstrates a fairly broad knowledge base, moderate depth of understanding, with small gaps; satisfactory expressive skills and significant mastery of scientific language; clearly discernible communication skills and critical thinking; good ability to summarize and more than acceptable graphical expression.

Distinguished (Grade 27-29):

The student demonstrates a very broad knowledge base, well-rounded, with only minor gaps; notable expressive skills and a high command of scientific language; presents topics clearly using appropriate language, with excellent ability to summarize and use graphical expression.

Excellent (30 - 30 with honors):

The student has a broad and in-depth knowledge base, excellent expressive skills, and a high command of scientific language; excellent communication skills, a strong aptitude for making connections between different topics; excellent ability to summarize and great familiarity with graphic expression. Honors is awarded to candidates who are significantly above average and demonstrate excellence in all aspects considered.

Learning assessment may also be conducted online, if circumstances require it.

Information for students with disabilities and/or learning disabilities:

To ensure equal opportunities and in compliance with current laws, interested students may request a personal interview in order to plan any compensatory and/or dispensatory measures based on

educational objectives and specific needs.

Students can also contact the CInAP (Centro per l’integrazione Attiva e Partecipata — Servizi per le Disabilità e/o i DSA, (https://www.cinap.unict.it/content/referenti) and referring teacher (prof.ssa Santina Chiechio email: santina.chiechio@unict.it) within of department.

Exam Dates

Exam dates are published on the Degree Program website: https://www.dsf.unict.it/it/corsi/lm-13/calendario-esami

Examples of multiple-choice questions.

1. Activation of the M₂ and M₄ cholinergic receptors causes:

o the activation of adenylate cyclase

o the inhibition of adenylate cyclase

o the opening of an ion channel of a receptor

o none of these.

2. One of the following statements regarding H₂ antihistamines is false:

o They are highly hydrophilic substances

o They are substances with a low partition coefficient

o They are substances with a high dipole moment

o They are always ionized on the basic group of the side chain.

Example of open-ended questions.

1. Describe the SARs of adrenergic agonists.

2. Write the structural formula of naloxone.

3. Describe the synthesis of diazepam.