Multifunctional tacrine derivatives in Alzheimer's disease.
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 M1- muscarinic receptors.
Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. anna.minarini@unibo.it
Anna
A
Minarini
Andrea
A
Milelli
Elena
E
Simoni
Michela
M
Rosini
Maria Laura
ML
Bolognesi
Chiara
C
Marchetti
Vincenzo
V
Tumiatti
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000627:therapeutic use; D015220:Calcium Channels / Q000378:metabolism; D002802:Cholinesterases / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000627:therapeutic use; D006801:Humans; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013619:Tacrine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000627:therapeutic use
D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D018697:Nootropic Agents; D043643:Receptor, Muscarinic M1; D016194:Receptors, N-Methyl-D-Aspartate; D013619:Tacrine; D002802:Cholinesterases; D053829:Amyloid Precursor Protein Secretases