Pharmacological and SAR analysis of the LINS01 compounds at the human histamine H 1 , H 2 , and H 3 receptors

Histamine is a transmitter that activates the four receptors H R to H R. The H R is found in the nervous system as an autoreceptor and heteroreceptor, and controls the release of neurotransmitters, making it a potential drug target for neuropsychiatric conditions. We have previously reported that the 1-(2,3-dihydro-1-benzofuran-2-yl)methylpiperazines (LINS01 compounds) have the selectivity for the H R over the H R. Here, we describe their pharmacological properties at the human H R and H R in parallel with the H R, thus providing a full analysis of these compounds as histamine receptor ligands through reporter gene assays. Eight of the nine LINS01 compounds inhibited H R-induced histamine responses, but no inhibition of H R-induced responses was seen. Three compounds were weakly able to inhibit H R-induced responses. No agonist responses were seen to any of the compounds at any receptor. SAR analysis shows that the N-methyl group improves H R affinity while the N-phenyl group is detrimental. The methoxy derivative, LINS01009, had the highest affinity.