Design and Synthesis of H3 Receptor Inverse Agonists with AchE Inhibitor Activity and QSAR Study of H3 Receptor Antagonists

Abstract

Currently, acetyl cholinesterase and N-methyl-D-aspartate antagonists are commercially available for the treatment of Alzheimer's disease (AD). Approach of using multifunctional inhibitors to reduce the side effects of available drugs is the main objective of this work. Presently, Histamine-3 (H3) receptor antagonists are used for the treatment of several neurodegenerative disorders such as Epilepsy, Alzheimer‘s and Parkinson‘s diseases. Both H3 and AchE inhibitors cure the symptoms of Alzheimer by enhancing the acetylcholine levels in the brain. But the mechanism of action involved in both the cases is different. Here, we propose histamine-3 antagonist with acetyl cholinesterase (AchE) inhibitor activity as a novel class of drugs which can be used to treat Alzheimer‘s disease with less adverse peripheral effects caused by excessive AchE inhibitor. Our present study can be divided into two parts. In the first part, homology modeled structure of H3 active site and available crystal structure of AchE was used to collect the information for pharmacophore identification. The important descriptors were identified based on comparative 2D-QSAR and 3D-QSAR study of 28 druggable compounds for H3 receptor collected from the literature. In the second part, five hybrid molecules were generated based on the pharmacophore of H3 receptor and known pharmacophore of AchE inhibitors. All five hybrid molecules were screened through ADME/tox filters. The hybrid molecule was validated through GOLD docking score in both AchE and H3 receptor. The best hybrid compound (hybrid-3) was then evaluated by molecular dynamics (MD) simulation in water solvent model using 3D model of human H3 receptor (build based on bovine rhodopsin structure).