OU-M. Pharmacy (Pharmaceutical Chemistry) Advanced Medicinal Chemistry 1st-Semester Model Paper

Time: 3 Hours

Max. Marks: 75

Note: Answer any five questions. All questions carry equal marks.

1(a) Give an account on various types of drug targets. (6 Marks)

Answer:

Drug targets are biomolecules that drugs interact with to produce their pharmacological effects. The main types of drug targets include:

  1. Receptors: Proteins or glycoproteins on cell membranes, intracellular sites, or within the cell. Example: G-protein-coupled receptors (GPCRs), ion channels.
  2. Enzymes: Biological catalysts that regulate metabolic processes. Example: Cyclooxygenase (COX), enzymes involved in neurotransmitter breakdown.
  3. Ion Channels: Pore-forming membrane proteins that regulate ion flow. Example: Voltage-gated sodium channels in the nervous system.
  4. Transporters: Proteins that transport molecules across membranes. Example: Sodium-potassium ATPase pump, serotonin transporter.
  5. DNA/RNA: Nucleic acids that drugs can interact with to inhibit replication or transcription. Example: Anticancer drugs like doxorubicin.
  6. Protein-Protein Interactions: Targeting specific interactions between proteins that are important in diseases. Example: Inhibitors of p53-MDM2 interactions.

1(b) Discuss theories of drug-receptor interactions. (9 Marks)

Answer:

Drug-receptor interactions are essential for drug activity. Several theories explain these interactions:

  1. Lock and Key Theory:
    • Proposed by Emil Fischer in 1894.
    • The receptor and drug have complementary shapes, like a lock and key.
    • The drug fits into the receptor’s binding site perfectly, producing a biological effect.
  2. Induced Fit Theory:
    • Proposed by Daniel Koshland in 1958.
    • Suggests that the receptor undergoes a conformational change upon drug binding.
    • The drug fits into the receptor’s active site, but the receptor also adapts to accommodate the drug.
  3. Occupancy Theory:
    • The drug’s effect is proportional to the number of receptors occupied by the drug.
    • It assumes that all receptors must be occupied to produce a maximal response.
  4. Rate Theory:
    • The biological response is proportional to the rate of drug-receptor complex formation, not just occupancy.
    • Faster binding of the drug to the receptor leads to a quicker response.
  5. Allosteric Theory:
    • Involves the concept of allosteric sites where drugs can bind to the receptor and cause a change in receptor function, either enhancing or inhibiting its activity.

2(a) Discuss lead optimization in drug discovery. (8 Marks)

Answer:

Lead optimization is the process of refining a lead compound to enhance its drug-like properties. This involves:

  1. Improving Potency: Modifying the structure to increase binding affinity to the target receptor or enzyme.
  2. Enhancing Selectivity: Modifying the compound to reduce off-target effects and increase specificity to the desired receptor or enzyme.
  3. Improving Pharmacokinetics: Optimizing the drug’s absorption, distribution, metabolism, and excretion (ADME) properties to improve bioavailability and reduce toxicity.
  4. Reducing Toxicity: Eliminating functional groups that may cause adverse effects or reducing the compound’s reactivity.
  5. Enhancing Stability: Ensuring that the compound remains stable under physiological conditions.
  6. Synthesis Feasibility: Ensuring that the compound can be synthesized cost-effectively and in large quantities.

2(b) Give an account on pro-moieties for various functional groups in prodrug design. (7 Marks)

Answer:

Prodrugs are pharmacologically inactive compounds that undergo metabolic conversion in the body to release the active drug. Pro-moieties are attached to the active drug molecule to improve its properties. Examples of pro-moieties include:

  1. Acyl Groups: Commonly used to modify alcohols or amines in prodrug design. Hydrolysis of the ester or amide bond releases the active drug.
    • Example: Diphenhydramine (antihistamine) as a prodrug that undergoes hydrolysis.
  2. Phosphate Esters: Used to modify hydroxyl or amine groups, making the prodrug more water-soluble and improving absorption.
    • Example: Fosphenytoin (anticonvulsant).
  3. Aryl Groups: Used to mask functional groups to improve lipophilicity and bioavailability.
    • Example: Valacyclovir (antiherpetic) is a prodrug of acyclovir.
  4. Amino Acid Derivatives: Used for improving solubility and targeting the drug to specific tissues, often in peptide drugs.
    • Example: Gleevec (Imatinib) uses amino acid pro-moieties.

3(a) What is hypertension? Give the classification of antihypertensive agents with examples. (8 Marks)

Answer:

  • Hypertension: A condition where blood pressure consistently exceeds 140/90 mm Hg. It is a major risk factor for cardiovascular diseases, including heart attack and stroke.
  • Classification of Antihypertensive Agents:
  1. Diuretics: Increase urine output to reduce blood volume and lower blood pressure.
    • Example: Hydrochlorothiazide, Furosemide.
  2. Beta Blockers: Reduce heart rate and cardiac output, leading to reduced blood pressure.
    • Example: Atenolol, Metoprolol.
  3. ACE Inhibitors: Inhibit angiotensin-converting enzyme, leading to vasodilation and reduced blood pressure.
    • Example: Enalapril, Lisinopril.
  4. Angiotensin II Receptor Blockers (ARBs): Block the effects of angiotensin II, causing vasodilation.
    • Example: Losartan, Valsartan.
  5. Calcium Channel Blockers: Inhibit calcium entry into cells, causing vasodilation and a reduction in heart rate.
    • Example: Amlodipine, Diltiazem.
  6. Alpha Blockers: Block alpha-1 adrenergic receptors, leading to vasodilation.
    • Example: Prazosin, Doxazosin.

3(b) Explain how the chirality of drugs is important for its pharmacological activity. (7 Marks)

Answer:

Chirality refers to the property of a molecule that makes it non-superimposable on its mirror image. The chirality of drugs is crucial for the following reasons:

  1. Receptor Binding: Drugs often interact with specific receptors or enzymes in a chiral manner. Only one enantiomer of a drug may fit the receptor site, leading to greater potency or efficacy.
    • Example: The (S)-enantiomer of Albuterol is more effective in treating asthma than the (R)-enantiomer.
  2. Pharmacokinetics: Enantiomers may have different absorption, distribution, metabolism, and excretion profiles. One enantiomer may be metabolized more quickly or slowly than the other.
    • Example: Warfarin exists as two enantiomers, with the (S)-enantiomer being more potent than the (R)-enantiomer.
  3. Toxicity: One enantiomer may be toxic or produce adverse effects, while the other is therapeutically effective.
    • Example: The (S)-enantiomer of thalidomide is effective as a sedative, while the (R)-enantiomer causes teratogenic effects.

4(a) Define drug resistance and discuss the mechanisms of antibiotic drug resistance. (8 Marks)

Answer:

  • Drug Resistance: A phenomenon where microorganisms such as bacteria, viruses, fungi, and parasites evolve to withstand the effects of drugs that once killed or inhibited them.
  • Mechanisms of Antibiotic Resistance:
    1. Enzymatic Inactivation: Bacteria produce enzymes that degrade the antibiotic.
      • Example: Beta-lactamases inactivate penicillins.
    2. Alteration of Drug Target: Mutations in the bacterial target site prevent the antibiotic from binding.
      • Example: Methicillin-resistant Staphylococcus aureus (MRSA) alters penicillin-binding proteins.
    3. Efflux Pumps: Bacteria can pump out antibiotics before they have a chance to act.
      • Example: Pseudomonas aeruginosa uses efflux pumps to expel antibiotics.
    4. Reduced Permeability: Bacteria reduce the influx of antibiotics into the cell.
      • Example: Gram-negative bacteria have an outer membrane that limits drug entry.

4(b) Classify anticonvulsants with examples and discuss the SAR of Benzodiazepines. (7 Marks)

Answer:

  • Classification of Anticonvulsants:
    1. Barbiturates: Enhance GABAergic activity.
      • Example: Phenobarbital.
    2. Benzodiazepines: Increase GABA binding to its receptor.
      • Example: Diazepam, Clonazepam.
    3. Hydantoins: Inhibit sodium channels.
      • Example: Phenytoin.
    4. Succinimides: Inhibit calcium channels.
      • Example: Ethosuximide.
    5. Carboxamides: Inhibit sodium channels.
      • Example: Carbamazepine.
  • SAR of Benzodiazepines:
    • The core structure consists of a benzene ring fused to a diazepine ring.
    • Substitution at position 7 with an electronegative group (such as chlorine) enhances activity.
    • Modifications at positions 1, 3, and 5 affect the potency, sedative, and anxiolytic properties.

5(a) Give an account on enzyme inhibitors in medicine and basic research. (8 Marks)

Answer:

Enzyme inhibitors are crucial in medicine and research for controlling diseases that involve overactive enzymes or to study enzyme mechanisms.

  1. Therapeutic Enzyme Inhibitors:
    • ACE Inhibitors: Used in hypertension to block the conversion of angiotensin I to angiotensin II. Example: Captopril.
    • Protease Inhibitors: Used to treat viral infections by inhibiting viral proteases. Example: Ritonavir (HIV).
    • Statins: Inhibit HMG-CoA reductase to lower cholesterol levels. Example: Atorvastatin.
  2. Research Enzyme Inhibitors:
    • Used to study enzyme function and mechanism, including specific inhibitors for proteases, kinases, and phosphatases.

5(b) Discuss non-covalently binding enzyme inhibitors and their pharmacological significance. (7 Marks)

Answer:

Non-covalently binding enzyme inhibitors interact with enzymes through reversible interactions like hydrogen bonds, van der Waals forces, and hydrophobic interactions. These inhibitors do not form covalent bonds with the enzyme and can dissociate.

  • Pharmacological Significance:
    1. Reversibility: These inhibitors can be easily removed from the enzyme, allowing for temporary inhibition.
    2. Selectivity: Non-covalent inhibitors can be designed to selectively target specific enzyme isoforms, reducing side effects.
    3. Lower Toxicity: Since they don’t permanently modify enzymes, they generally have a lower toxicity profile.
    4. Examples: Ibuprofen (COX inhibitor), Methotrexate (Dihydrofolate reductase inhibitor).

6(a) Define peptidomimetics and discuss the advantages of them over peptide drugs. (8 Marks)

Answer:

  • Peptidomimetics: These are synthetic compounds that mimic the structure and function of peptides but with modifications that enhance their stability, bioavailability, and efficacy.
  • Advantages Over Peptide Drugs:
    1. Improved Stability: Peptidomimetics are less susceptible to enzymatic degradation compared to peptides.
    2. Better Oral Bioavailability: Peptides are often degraded in the gastrointestinal tract, while peptidomimetics can be designed for better absorption.
    3. Enhanced Membrane Permeability: Peptidomimetics can be engineered to cross biological membranes more effectively.
    4. Lower Immunogenicity: Peptidomimetics are less likely to provoke an immune response.

6(b) Discuss unnatural amino acids used in peptidomimetic drug design. (7 Marks)

Answer:

Unnatural amino acids are used in peptidomimetic design to enhance the properties of peptides, such as stability, specificity, and bioavailability.

  1. D-Amino Acids: Used to reduce enzymatic degradation by proteases.
  2. Fluorinated Amino Acids: Improve binding affinity and metabolic stability.
  3. Aromatic Amino Acids: Enhance the hydrophobic interactions in binding to receptors.
  4. β-Amino Acids: Replace natural amino acids to stabilize the structure or introduce conformational rigidity.

7(a) Discuss the chemistry of prostaglandins and leukotrienes. (8 Marks)

Answer:

  • Prostaglandins: Lipid compounds derived from arachidonic acid. They play roles in inflammation, blood clotting, and vasodilation. Prostaglandins are produced via the cyclooxygenase (COX) pathway.
    • Chemistry: Prostaglandins have a 20-carbon skeleton, with a cyclopentane ring and various functional groups (hydroxyl, keto).
  • Leukotrienes: Another class of eicosanoids produced from arachidonic acid via the lipoxygenase pathway. They are involved in allergic reactions and inflammation.
    • Chemistry: Leukotrienes have a structure featuring a conjugated triene system, which is crucial for their biological activity.

7(b) Explain the concept of bio-isosterism. (7 Marks)

Answer:

Bio-isosterism is the concept of replacing one atom or group in a drug molecule with another that has similar size, shape, and electronic properties, to modify the drug’s pharmacokinetic and pharmacodynamic properties.

  • Types of Bio-isosterism:
    1. Classical Bio-isosterism: Replacement of atoms or groups without affecting the drug’s biological activity.
      • Example: Replacing a hydrogen atom with a fluorine atom.
    2. Non-classical Bio-isosterism: Structural changes that affect the molecule’s conformation but maintain the biological effect.

8. Write a short note on:

(a) Beta Blockers (8 Marks)

Beta Blockers are a class of drugs that block beta-adrenergic receptors, which are part of the sympathetic nervous system. These drugs primarily affect the heart, as they block the effects of epinephrine (adrenaline) and norepinephrine on beta-1 receptors.

  • Mechanism of Action: Beta blockers work by binding to the beta-adrenergic receptors (β1, β2, and β3) on the surface of cells, particularly in the heart, blood vessels, lungs, and kidneys. By blocking these receptors, they inhibit the normal action of catecholamines (epinephrine and norepinephrine) and decrease the heart rate, myocardial contractility, and overall cardiac output. This leads to a reduction in blood pressure and heart rate.
  • Types:
    1. Non-selective Beta Blockers: These block both β1 (heart) and β2 (lungs, blood vessels) receptors.
      • Example: Propranolol, Nadolol.
    2. Selective Beta Blockers: These primarily block β1 receptors (mainly in the heart), with minimal effects on β2 receptors.
      • Example: Atenolol, Metoprolol, Bisoprolol.
  • Clinical Uses:
    • Hypertension: Beta blockers are commonly used to treat high blood pressure by reducing the heart’s workload and lowering blood pressure.
    • Angina Pectoris: They decrease myocardial oxygen demand by slowing the heart rate and reducing contractility.
    • Heart Failure: Some beta blockers, such as Carvedilol and Metoprolol, are used in heart failure to reduce the progression of the disease and improve heart function.
    • Arrhythmias: Beta blockers help stabilize heart rhythms, particularly in atrial fibrillation and ventricular arrhythmias.
    • Anxiety: Beta blockers are sometimes used to treat the physical symptoms of anxiety, such as tremors and palpitations.
  • Adverse Effects:
    • Bradycardia: Slowing of the heart rate can lead to dizziness or fainting.
    • Fatigue: Common side effect due to reduced heart rate and blood pressure.
    • Bronchospasm: Non-selective beta blockers can exacerbate asthma or chronic obstructive pulmonary disease (COPD).
    • Cold Extremities: Reduced blood flow can cause hands and feet to feel cold.

(b) HIV Protease Inhibitors (7 Marks)

HIV Protease Inhibitors are antiretroviral drugs used to treat HIV (Human Immunodeficiency Virus) infection. These inhibitors target the HIV protease enzyme, which is essential for the replication of the virus.

  • Mechanism of Action: HIV protease is an enzyme responsible for cleaving the large viral polyproteins into smaller, functional proteins, which are necessary for assembling new virus particles. By inhibiting HIV protease, these drugs prevent the virus from maturing and producing infectious viral particles, effectively halting the replication cycle. Protease inhibitors block the active site of the enzyme, thus preventing the cleaving process.
  • Clinical Uses: HIV protease inhibitors are a crucial part of Highly Active Antiretroviral Therapy (HAART), which combines multiple antiretroviral drugs to effectively suppress HIV replication and reduce viral load. They are used in both treatment and prevention of HIV infection.
    • Examples:
      1. Ritonavir: Often used in combination with other protease inhibitors to enhance their pharmacokinetic profile.
      2. Lopinavir: A combination of Lopinavir and Ritonavir is commonly used as a first-line therapy.
      3. Atazanavir: A newer protease inhibitor with a lower risk of side effects compared to older agents.
      4. Darunavir: Another commonly used protease inhibitor that is effective against resistant strains of HIV.
  • Adverse Effects:
    • Gastrointestinal issues: Nausea, vomiting, and diarrhea are common side effects.
    • Hyperlipidemia: Elevated cholesterol and triglyceride levels can occur with long-term use.
    • Liver Toxicity: Hepatotoxicity is a concern, especially with drugs like Ritonavir.
    • Drug Interactions: HIV protease inhibitors are metabolized by the liver enzyme CYP450, and they can interact with many other drugs, potentially altering their effectiveness or leading to side effects.
  • Resistance: Over time, HIV can develop resistance to protease inhibitors, typically due to mutations in the protease gene. To combat this, combinations of protease inhibitors and other classes of antiretroviral drugs are often used to prevent resistance and improve treatment outcomes.