Effects of Antihistamines on the Function of Human Alpha-7 Nicotinic Acetylcholine Receptors

Seyedeh Soha Khanian


The effect of histamine H1 receptor (H1R) antagonists (antihistamines), namely, promethazine (PMZ), orphenadrine (ORP), chlorpheniramine (CLP), pyrilamine (PYR), diphenhydramine (DPH), cetirizine (CTZ), and triprolidine (TRP) were tested on the function of the cloned α7subunit of the human nicotinic acetylcholine receptor (α7-nAChR) expressed in Xenopus oocytes using the two-electrode voltage-clamp technique. Antihistamines inhibited the α7-nAChR in the order of PYR > CLP > TRP > PMZ > ORP ≥ DPH ≥ CTZ. Among antihistamines, PYR showed highest reversible inhibition of acetylcholine (100 µM) - induced current with IC50 value of 6.2 µM. In contrast, the standard H2-H4R antagonists, cimetidine (CMT), ranitidine (RNT), nizatidine (NZT), clobenpropit (CLB), ciproxifan (CPR), pitolisant (PIT), and JNJ-7777120 (JNJ) when tested at high concentration (10 µM) showed negligible inhibition of α7-nAChR. Further experiments using PYR, the strongest inhibitor of α7-nAChR indicated that PYR inhibition was not dependent on the membrane potential and could not be reversed by increasing acetylcholine concentrations suggesting a non-competitive inhibition of nicotinic receptors. In line with functional experiments, docking studies indicated that PYR can potentially bind allosterically with the α7 transmembrane domain. Our results indicate that first generation HIR antagonists inhibit the function of human α7-nAChR, with varying potencies, and emphasize the importance of α7-nAChR for future harmacological/toxicological profiling of these antihistamines