Multifunctional Tacrine Derivatives in Alzheimer’s Disease

Anna      Minarini; Andrea      Milelli; Elena      Simoni; Michela      Rosini; Maria   Laura   Bolognesi; Chiara      Marchetti; Vincenzo      Tumiatti

doi:10.2174/15680266113139990136

Abstract

Tacrine (1) was the first acetylcholinesterase inhibitor (AChEI) introduced in therapy for the treatment of Alzheimer’s disease (AD), but similarly to the most recent approved AChEIs and memantine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, it does not represent an effective drug in halting the progression of AD. The continuous research in this field has contributed to delineate AD as a multifactorial syndrome with several biological targets involved in its etiology. On these bases, the development of new effective therapeutics becomes crucial and the design of molecules that address more than one specific AD target should represent thus a succeeded strategy for AD treatment. This review will focus on and summarize multifunctional 1 derivatives starting from our last paper published on the same topic in 2010. In the last three years, the design and synthesis of 1 homo- and heterodimers, as well as of 1-hybrid structures for AD therapy, was aimed mainly to discover safer drugs, with decreased hepatotoxicity in comparison to 1, taking also into account the multifactorial pathogenesis of the disease. Most of these new hetero/homo-dimers and/or hybrids of 1, although addressed mainly to acetylcholinesterase (AChE) and Aβ aggregation inhibition, are able to hit additional targets relevant to AD, among which, β-secretase (BACE1), reactive oxygen species (ROS), calcium channels, NMDAR and M_1- muscarinic receptors.

Keywords: Dual binding acetylcholinesterase inhibitors, multi-target-directed ligands (MTDLs), neurodegenerative diseases, tacrine, tacrine homodimers, tacrine heterodimers, tacrine hybrids.

« Previous Next »