Investigation of the histamine H3 receptor binding site. Design and synthesis of hybrid agonists with a lipophilic side chain.
J Med Chem
; 53(17): 6445-56, 2010 Sep 09.
Article
en En
| MEDLINE
| ID: mdl-20690643
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Piperidinas
/
Piridinas
/
Agonistas de los Receptores Histamínicos
/
Receptores Histamínicos H3
/
Imidazoles
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2010
Tipo del documento:
Article
País de afiliación:
Japón