Dual targeting agents for A β plaque/P-glycoprotein and Aβ plaque/nicotinic acetylcholine α4β2* receptors—potential approaches to facilitate Aβ plaque removal in Alzheimer’s disease brain

We report here development of dual targeting agents with affinity for Aβ plaque/P-glycoprotein (Pgp) and Aβ plaque/α4β2* nicotinic acetylcholine receptors (nAChR). These novel dual agents may be able to efflux Aβ plaques via the paravascular (glymphatic) pathways. Ferulic acid (FA), ferulic acid ethyl ester (FAEE), and curcumin (CUR) were used for Aβ plaques, fexofenadine (FEX) was used as substrate for Pgp and nifrolidine (NIF) was used for α4β2* nAChRs. Aβ plaque/α4β2* nAChR dual agent, FA-NIF (GKS-007) exhibited IC50 = 3–6 nM for α4β2* nAChRs in [3H]cytisine-radiolabeled thalamus and frontal cortex in rat brain slices. In postmortem human AD frontal cortex, A β plaques labeled with [3H]PIB, FEX-CUR showed a 35% reduction in gray matter (GM)/white matter (WM) [3H]PIB binding, while CUR alone showed a 50% reduction. In vivo biodistribution studies are required of the A β−Pgp and Aβ-α4β2* nAChRs dual targeting agents in order to evaluate their potential as therapeutic approaches for reducing brain Aβ plaques.
Source: Medicinal Chemistry Research - Category: Chemistry Source Type: research