Since its discovery in 1983, followed by gene cloning in 1999, the histamine
H3 receptor served as an outstanding target for drug discovery. The wide spectrum of possible
therapeutic implications makes H3R's one of the most researched areas in the vast
GPCR ligands field - started from imidazole containing ligands, through various successful
imidazole replacements, with recent introduction of Wakix® to pharmaceutical market.
One such replacement is piperazine moiety, a significant versatile scaffold in rational
drug design for most of the GPCR ligands. Therefore, herein, we review ligands built on
piperazine, as well as its seven membered analogue azepine, that target H3R’s and their
potential therapeutical applications, in order to elucidate the current state of the art in this
vast field. Due to a high level of structural divergence among compounds described
herein, we decided to divide them into groups, where the key division element was the
position of nitrogen basicity decreasing moieties in (homo)piperazine ring. Paying attention
to a number of published structures and their overall high biological activity, one can
realize that the (homo)piperazine scaffold bids a versatile template also for histamine H3
receptor ligands. With two possible substitution sites and therefore a number of possible
structural combinations, piperazine derivatives stand as one of the largest group of high
importance among H3R ligands.
Purification of a histamine H3 receptor negatively coupled to phosphoinositide turnover in the human gastric cell line HGT1.
