Histamine H3-receptor isoforms

Abstract

Increasing evidence supports a role for HA as a neurotransmitter and neuromodulator in various brain functions, including emotion, cognition, and feeding. The recent cloning of the histamine H3 receptor allowed for the subsequent cloning of a variety of H3 receptor isoforms from different species as well as the H4 receptor. As a result a wide variety of H3-receptor isoforms are now known that display differential brain expression patterns and signalling properties. These recent discoveries are discussed in view of the growing interest of the H3 receptor as a target for the development of potential therapeutics.

Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

“…Main interactions between FUB836 and the hH 3 R binding site are listed in the Result section. Another residue in the hH 3 R, yet not interacting with FUB836, was methionine 6.55, which stabilised the second aromatic ring in biphenylic systems, such as A-331440 (results not shown) [50].…”

“…All analyses of experimental data were performed with the Prism 4 program (GraphPad Software, San Diego, CA). K i values were calculated using the Cheng and Prusoff equation [39] and a K D of 1,081 nM for [ 3 …”

“…Recently, several review articles have been published on the histamine H 3 receptor, [2] H 3 R isoforms, [3,4] on H 3 R antagonists [5,6] and agonists, [7] which summarise the current knowledge on this receptor. Briefly, the hH 3 R is a GPCR protein expressed presynaptically in several regions of the central and peripheral nervous system where it functions either as an autoreceptor regulating the release of histamine from histaminergic neurons or as an heteroreceptor regulating the release of several other neurotransmitters.…”

“…In order to find new hH 3 R ligands, initially, derivatives of the intrinsic ligand histamine were generated leading to the class of imidazolecontaining compounds [for a review see 6,7]. Due to several potential drawbacks of the imidazole-moiety (interaction with P450 enzymes, substrate of the inactivating enzyme, histamine N s -methyl transferase, and low CNS penetration 1 ) great effort was put into the replacement of this moiety, resulting in the nowadays heterogeneous class of non-imidazole ligands containing mostly piperidine, pyrrolidine or structurally related groups [10, for a review see 5,7].…”

“…Several in silico studies have already been carried out on the hH 3 R focusing however mainly on the placement of ligands in the binding pocket and on the derivation of a putative binding site for reasoning the design of new compounds rather than on an automatic screening for new compounds. In 2000 De Esch et al [16,17] published a study on imidazole-containing hH 3 R ligands and proposed a pharmacophore model consisting of a common anchor site for the imidazole moiety which was expected to interact with E5.46 in helix 5, and two lipophilic pockets. At the same time branched compounds published by Schering in the patent application WO00/53596 confirmed the existence of two lipophilic pockets.…”