Histamine and its receptor
PHAR3014 Medicinal Chemistry & Drug Design
H1-receptors are coupled to inositol phospholipid hydrolysis thus increasing the intracellular concentration of free calcium ions, illustrated in Figure 11. In peripheral tissues, the H1 subclass of histamine receptor mediates the contraction of smooth muscles, increase the capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neurotransmitter in the central nervous system (CNS).
H1-receptor
Histamine was found to form interactions to the third (TM3) and fifth (TM5) transmembrane domains of receptor proteins. The affinity of histamine to the H1-receptor is determined by the presence of ionic interaction of the protonated ethylamine side chain with the aspartic acid residue in TM3 and a hydrogen bond between Nτ-nitrogen of the imidazole ring and asparagine in TM5.
H1-receptor is blocked by antihistamine to cause sedation. Due to its lipophilicity in antihistamine, it can pass through the blood-brain barrier to induce an effect against the sleep-wake cycle (Choi et al., 2013). Mepyramine remains the choice of selective H1 antagonist due to its high affinity and good receptor selectivity. Another example of H1 antagonist is the geometric isomer trans-triprolidine, which has a Kd of 0.1 nM. There is no highly selective agonist for H1-R, but 2-methylhistamine and 2-thiazoylethylamine have shown some selectivity.
This receptor serves as the main target for many clinical drugs on the market. It plays an important role in the modulation of internal body clock by altering the neurochemistry in the brain to induce awakeness once bound to histamine. Besides, histamine action on its receptor is said to induce hunger in mammals. The effects of histamine on H1-R is mainly excitatory. On the contrary, excess activation of this receptor triggers the symptoms of allergies such as hayfever, conjunctivitis and urticaria.
SAR of H1-R
Figure 13 SAR of histamine and the asparagine side chain of the receptor.
Figure 12 From left; hay fever, conjunctivitis and urticaria.
Figure 11 Mediation of H1 receptor pathways.
(Adapted from Choi et al., (2013).