Peripheral binding site, cholinesterases

A series of novel l, 3-dihydroxyxanthone Mannich base derivatives were synthesized, structure elucidated, and evaluated for anticholinesterase activity. Most of the target compounds exhibited moderate to good inhibitory activities with the IC50 values at micromole level concentration against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among them, 2 - ((diethylamino )methyl) -1 -hydroxy- 3 - (3 -methylbut-2-enyloxy) -9H-xanthen-9-one showed potent inhibitory activity against AChE and the best inhibitory activity against BuChE. The Mannich base derivatives were likely to bind to the active site (AS) and the peripheral anionic site (PAS) of cholinesterases [169]. 

Cholinesterases also have a peripheral, allosteric site that can reversibly bind substrates and other ligands. This site has no catalytic activity. However, binding of a ligand to the site can cause either inhibition or activation of the enzyme. 

Note that the kinetic interactions of substrates with AChE and BuChE are in reality more complex than portrayed in Fig. 5. Both cholinesterases have been shown to display substrate inhibition and activation, depending on the incubation condilion.s (Masson et ai., 2004). probably as a result of the presence of a binding site separate from the active site, termed the peripheral anionic site (Changeux. 1966 Taylor and Radic, 1994 Barak et ai., 1995 Soreq and Seidman,... 

Saxena, A., Fedorko, J.M., and Vinayaka, C.R. etal 2003. Aromatic amino-acid residues at the active and peripheral anionie sites eontrol the binding of F2020 (AriceptR) to cholinesterases. EurJBiochem, 270(22) 4447-4458. 

Phenyl tetrahydroisoquinoline scaffold was selected as it was proven to be a convenient peripheral site binder [27]. There is a growing interest in developing multitarget-directed drugs and particularly new potent dual-binding site, AChE inhibitors are able to exert a dual action [33] (inhibition of cholinesterase activity and inhibition of AChE-mediated Ap deposition) [34]. The results of the m-AChE-directed syntheses of heterodimeric huprine-based inhibitors are summarized vide Table 2.1). 

---