Histamine and its receptor
PHAR3014 Medicinal Chemistry & Drug Design
Histamine receptors are protein found in various parts of the body that binds with histamine to produce a specific effect in the body. They belong to G protein-coupled receptor (GPCR) family, and there are four sub-types named chronologically as H1, H2, H3 and H4. They transduce extracellular signals via the G-proteins, Gq, Gs, Gi/o and Gi/o respectively (Dickenson et al., 2013).
GPCR serves as a drug target to up one-fourth of marketed pharmaceutical prescriptions explains why there is a variety of agonist and antagonist targeting this receptor. Due to its relationship with GPCR, histamine induces the production of inositol phosphate in several tissues such as the brain, airway smooth muscle and heart tissue.
Due to excess histamine produced during inflammation, the first compound of antihistamine, piperoxan (933F) was reported in 1937 with the evidence of its blocking the effect of histamine on guinea-pig ileum (Parsons & Ganellin, 2006). Antihistamine has been widely used in treating the symptoms of allergic reactions such as seasonal hay-fever, allergy rhinitis and conjunctivitis. Acute and chronic urticaria, dermatoses and pruritis respond well to antihistamine. Sedation and drowsiness are the main side effects of the first-generation antihistamine. Lipophilicity of antihistamine enhances its penetration into the blood-brain barrier.
As for histamine receptor, Aspartic acid (Asp) plays its role. It is essential for binding of histamine or its antagonist, by providing a negative counter-ion for the protonated amine group of the ligand. Residues in another transmembrane region, TM5, have also been shown to be required for histamine binding. Chromatographic experiments were used to study SAR of agonist and antagonist drugs with histamine receptor.
Figure 8 Aspartic acid at physiological pH
Figure 9 Pocket receptor of histamine and its amino acid side chain
Discovery of antihistamine
Figure 10 3-D conformer of Piperoxan, red atoms are oxygen while blue atom is nitrogen.