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Medicinal Chemistry Research

, Volume 27, Issue 6, pp 1634–1646 | Cite as

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

  • Gurleen K. Samra
  • Kenneth Dang
  • Heather Ho
  • Aparna Baranwal
  • Jogeshwar Mukherjee
Original Research

Abstract

Alzheimer’s disease (AD) affects 10% of people older than 65 and is characterized by a progressive loss of cognitive function with an abnormal accumulation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFT) in the brain. Efforts to reduce brain Aβ plaques continue to be investigated as a therapeutic approach for AD. 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, Aβ 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 Aβ−Pgp and Aβ-α4β2* nAChRs dual targeting agents in order to evaluate their potential as therapeutic approaches for reducing brain Aβ plaques.

Keywords

Alzheimer’s disease Plaque removal Ferulic acid Curcumin Nifene PET imaging 

Notes

Acknowledgements

This research was financially supported by a grant from NIH/NIA AG029479 (J.M.). We like to thank Banner Sun Health Research Institute, Sun City, Arizona for the postmortem human brain tissue samples, and Christopher Liang for technical assistance.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Preclinical Imaging, Department of Radiological SciencesUniversity of California-IrvineIrvineUSA
  2. 2.Department of Biomedical EngineeringUniversity of California-IrvineIrvineUSA
  3. 3.West Virginia School of Osteopathic MedicineLewisburgUSA

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