Investigation of the Histamine H3 Receptor Binding Site. Design and Synthesis of Hybrid Agonists with a Lipophilic Side Chain

Abstract

As a part of our search for novel histamine H3 receptor agonists, we designed and synthesized hybrid compounds in which the lipophilic (4'-alkylphenylthio)ethyl moiety of a novel H3 receptor agonist, 4-(2-(4'-tert-butylphenylthio)ethyl)-1H-imidazole (1), was incorporated into N(alpha)-methylhistamine, immepip, and immethridine derivatives. These hybrid compounds were expected to interact concurrently with the histamine-binding site and a putative hydrophobic region in the H3 receptor. Among them, piperidine- and pyridine-type derivatives displayed partial agonist activity, and (S)-4-(1-(1H-imidazol-4-yl)-2-(4-(trifluoromethyl)phenylthio)ethyl)piperidine (36) was identified as a potent H3 agonist. We performed computational docking studies to examine the binding mode of the agonists. The results indicated that immepip interacts with the key residues, Asp114 and Glu206, in a different manner from histamine. The binding mode of 36 to these residues is similar to that of immepip, and the lipophilic tail of 36 has an additional interaction with a hydrophobic region in transmembrane helix 6 of the receptor. These results indicated that 36 served as a useful tool for studies on receptor-agonist interactions and drug design.

The Histamine H3Receptor: Structure, Pharmacology, and Function

“…Residues important for agonist recognition are colored in pink. Oldham and Hamm, 2007;Ishikawa et al, 2010;Kim et al, 2011;Kuramasu et al, 2011); however, three rat isoforms (rH 3 R 497 , rH 3 R 465 , and rH 3 R 449 ) that do not possess TM7, but do have an extracellular CT of 105 aa without homology to the functional isoforms, reduce the cell surface expression of the rat H 3 R 445 upon coexpression in COS-7 cells (Bakker et al, 2006). The expression and signaling of functional H 3 Rs could thus be regulated by isoforms incapable of triggering the signaling pathways described to follow.…”

A structural chemogenomics analysis of aminergic GPCRs: lessons for histamine receptor ligand design

“…Interestingly, the isoquinoline fragment 69 only binds H 1 R, while several chemically related quinazoline and aminopyrimidine‐containing fragment‐like compounds have been reported to show submicromolar affinities for H 3 R and H 4 R (Smits et al ., 2008; 2012; de Graaf et al ., ; Schultes et al ., ), illustrating how small changes in heteroaromatic ring systems can affect binding of specific histamine receptors. Stereoisomers 71 and 72 represent interesting examples of a stereoisomer specific histamine receptor selectivity switch (Figure ) (Ishikawa et al ., ). While 71 has a 4‐fold selectivity for H 1 R over H 3 R (and 6‐fold selectivity over H 4 R), 72 has a 20‐fold selectivity for H 3 R over H 1 R (and 93‐fold selectivity over H 4 R).…”

“…The symmetric distributions of complementary pharmacophore features in H2R, H3R and H4R binding sites (i.e. D 3.32 in TM3 and D98 5.42 /E206 5.46 /E182 5.46 in TM5) and histamine receptor ligands that contain two basic groups, makes binding mode prediction challenging (Lorenzi et al, 2005;Schlegel et al, 2007;Jongejan et al, 2008;Kiss et al, 2008b;Ishikawa et al, 2010;Istyastono et al, 2011b;Schultes et al, 2012). The binding modes of several H4R ligands, including isothioureas (e.g.…”

A single‐point mutation (Ala280Val) in the third intracellular loop alters the signalling properties of the human histamine H3 receptor stably expressed in CHO‐K1 cells

“…Binding determinations indicated that the A280V mutation did not affect hH 3 receptor expression or its affinity for a series of selective ligands. The latter result was not unexpected because the mutation is not located on any of the receptor regions primarily involved in ligand binding, namely trans‐membrane domains 3, 5 and 6 (Uveges et al ., ; Ishikawa et al ., ; Kim et al ., ). In contrast, the mutant receptor was less efficacious to inhibit forskolin‐stimulated cAMP accumulation and to stimulate [ 35 S]‐GTPγS binding, indicating that the mutation did affect the signalling properties of the receptor.…”