CHE2MOC-Medicinal and Organic Chemistry - Science Assignment Help

Assignment Task

Task

Background: 

Histamine is a local hormone that is found in most tissues around the human body. It is found in particularly high concentrations in mast cells and is released rapidly and in large amounts from mast cells in the early phase of inflammation or an immune response.

Histamine primarily acts on the histamine receptor, designated by the letter H. Four sub-types of the histamine receptor have been identified, creatively named H1, H2, H3 and H4. For the purposes of this assignment, we will focus our attention on H1 and H2. 

When activated, H1 receptors are associated with classical allergy or hay fever symptoms like itch, weal and flare (reddening skin around a wound or bite), increased vasodilation (red, runny eyes) and rhinorrhoea (runny nose). 
When H2 receptors are activated, they stimulate the secretion of gastric acid, increase heart rate and increase force of heart contraction.  

The effects of histamine can be modulated by using drugs to block histamine from accessing its receptors. Although antihistamines were first discovered in 1937, it took until the 1980s for them to be used clinically. Antihistamines are a class of drug that are used to compete with histamine in binding to H receptors. They are commonly divided into first, second and third generation. 

First Generation antihistamines include diphenhydramine, pheniramine, chlorpheniramine, dexchlorpheniramine, promethazine and cyproheptadine. These drugs have the traditional antihistamine effects on runny eyes and nose. They also readily cross the blood-brain barrier and block the H1 receptor in the central nervous system, which plays a wakeful role in the sleep-wake cycle. The use of these drugs in practice is somewhat limited by the drowsiness that they can cause. 

First generation antihistamine: Diphenhydramine

Diphenhydramine was one of the first antihistamines used clinically. It is a first-generation antihistamine and is still commonly used in practice today. Consider the chemical structure of diphenhydramine:  

1. Each functional group of diphenhydramine may be important in binding the drug to the H1 receptor. Identify the functional groups on diphenhydramine and indicate the potential intermolecular interaction/s they may participate in.

2. As part of a ‘Structure Activity Relationship’ analysis on diphenhydramine, suggest structural modifications that will assess the mode of binding for each functional group. Provide rationale for your suggested modifications.

3. Indicate on diphenhydramine any groups that may readily donate protons (acid group) or readily accept protons (basic group). Given your response, suggest potential influences on the behaviour of the drug. 

Second generation antihistamine: Cetirizine and loratadine

4. Compare the structure of cetirizine and loratadine. Based on the functional groups and their pKa values, which of these compounds would you expect to have a higher excretion through the kidneys? Why? 

5. Based on the chemical structures provided above, which of cetirizine, loratadine and fexofenadine would you expect to cross the thick lipid blood-brain barrier? Why? 

6. Compare the chemical structure of diphenhydramine to that of the second generation antihistamines cetirizine, loratadine and fexofenadine. Propose a reason as to why second-generation antihistamines are less efficient in crossing the blood brain barrier than diphenhydramine and other first generation antihistamines.

Pharmacokinetic parameter: Inhibitory Constant Ki

7. Rank these antihistamines from the highest to the lowest affinity for the H1 receptors in this tissue sample. 

Clinical Applications of Pharmacokinetics.

8. Which of these antihistamines would be associated with the highest rate of adverse effects? Why? 

9. Your partner's grandmother suffers from terrible seasonal hay fever and wants an antihistamine. You are a caring in-law and are aiming for a positive outcome for the dear old lady. Which of the antihistamines from the above list will maximise the beneficial effects while minimising adverse effects? Why?

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