Pharmacophore Modeling of N1-alkyltheobromine as Histamine-H1 Receptor Antagonist

Abstract

Abstract-Previous studies worked on the evaluation a few alkylxanthine derivatives synthesized from theobromine, exhibiting micromolar activities of the compounds against histamine in vitro. The structure-activity relationships study showed that the elongation of alkyl group at N 1 of xanthine ring increased the tracheospasmolytic activity. This result opened the opportunity for alkylxanthine to be developed as antihistamine. Presently, we elucidate the mechanism of N 1 -alkylxanthine derivatives as antihistamine at a molecular level using pharmacophore modeling. The pharmacophore model was generated from a series of Histamine-H1 antagonists employing hydrogen bond acceptor (HBA), hydrogen bond donor (HBD) and two hydrophobic features and used as a search queries to map the N 1 -alkylxanthine derivatives as Histamine-H1 antagonist. The results showed that all the designed ligands can adopt the pharmacophore features model providing the insight understanding about the opportunities of the N 1 -alkylxanthine as Histamine-H1 antagonists.

Molecular Modeling of Histamine Receptors—Recent Advances in Drug Discovery

“…They were reported to be a promising template for designing novel non-sedating H 1 R antihistaminic agents [70]. Docking studies, using AutoDock, showed that derivatives of N 1 -alkyltheobromine, which exhibited H 1 R antihistaminic activity comparable to doxepin and less CNS depressant side effects than olapatadine, interacted electrostatically and formed hydrogen bonds with residues D 3.32 , Y 3.33 , S 3.36 , T 3.37 , K 5.39 and Y 6.51 [71]. In one study, quinoline derivative (QS-15), astemizole and diclofenac sodium have been shown to interact with residues D 3.32 , W 6.48 and F 6.52 [73].…”