1. (10 pts) Histidine can be decarboxylated in an enzyme-catalyzed reaction to f
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1. (10 pts) Histidine can be decarboxylated in an enzyme-catalyzed reaction to form histamine. When the body produces excess histamine, the singly positively charged histamine interacts with histamine receptor to causes the symptoms associated with the common cold and allergies. Chlortrimetron is one of antihistamines that were found to bind to the histamine receptor but not trigger the same response as histamine. This compound, however, is able to cross the blood-brain barrier and bind to receptors in the central nervous systems. Binding to receptors in central nervous systems causes drowsiness, the well-know side effect associated with antihistamines. To overcome the side effect of antihistamines, Allegra has been developed as one of nonsedating antihistamines. Cl NH 2 HO ?? ?? histamine fexofenadine (Allegra) chlorpheniramine (Chlortrimetron) (a) Rank and explain the basicity of the three nitrogen atoms in histamine. (b) Explain why Chlortrimetron is able to bind to the histamine receptor and also cross the blood-brai?n barrier. (c) Draw the structure of fexofenadine at physiological pH and explain why Allegra is a nonsedating antihistamine.Explanation / Answer
Histamine structure has 3 Nitrogen atoms. Aliphatic Nitrogen has more basic strength as it cannot delocalise negative charge whereas aromatic nitrogen atom with hydrogen is least basic as it has lone pair which is delocalised and thus it is not easily available for donation. Nitrogen atom of imidazole ring which donot have hydrogen atom is less basic than aliphatic nitrogen and is more basic than aromatic nitrogen having proton. Chlorpheniramine is a alkylamine, is an Histamine H1 antagonist or inverse histamine antagonist which is not structurally similar to histamine but binds to different sites of histamine receptor thereby reducing its effect. This binding produces opposite effect as that of histamine binding do and thus known as anti-histamine. It has sedating effect as it can cross blood-brain barrier. Allegra or fexofenadine is non-sedating, second generation antihistamine due to their limited penetration of blood brain barrier.
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