PHAR3819 Lecture Notes - Lecture 2: Imidazole, Side Chain, Histamine
23 Jul 2018
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Document Summary
N(pi) = closest to side chain, n(tele) = further away. Exists as a mixture of different ionic and uncharged tautomeric species. However is exists almost exclusively (96. 6%) as the monocationic conjugate species at physiological ph. Release acid into the stomach to digest food. Structure activity studies were carried out using analogues of histamine: heterocyclic ring containing n, tertiary n protonated. Having a positive charge in the terminal end is essential for agonist activity. Histamine acts with 2 sites; want to find something that binds to 3 sites. If we added an extra functionality, it would bind with the third site. Postulated that delocalised +ve charge could interact with a site on the receptor that the nh3+ of histamine can"t reach. Guanidine group = positive charge delocalises around the nitrogens. Extended analogues pushes the positive charge further away from the imidazole ring, preventing it from interacting with the agonist site. All these compounds where showing partial agonist activity not pure antagonist.
