Background: Multifactorial diseases such as Alzheimer's disease (AD) should be more efficiently tackled by drugs which hit multiple biological targets involved in their pathogenesis. We have recently developed a new family of huprine-tacrine heterodimers, rationally designed to hit multiple targets involved upstream and downstream in the neurotoxic cascade of AD, namely β-amyloid aggregation and formation as well as acetylcholinesterase catalytic activity. Objective: In this study, the aim was to expand the pharmacological profiling of huprine-tacrine heterodimers investigating their effect on muscarinic M 1 receptors as well as their neuroprotective effects against an oxidative insult. Methods: Sprague-Dawley rat hippocampus homogenates were used to assess the specific binding of two selected compounds in competition with 1 nM [ 3H]pirenzepine (for M 1 receptors) or 0.8 nM [ 3H]quinuclidinyl benzilate (for M 2 receptors). For neuroprotection studies, SHSY5Y cell cultures were subjected to 250 μM hydrogen peroxide insult with or without preincubation with some huprine-tacrine heterodimers. Results: A low nanomolar affinity and M 1/M 2 selectivity has been found for the selected compounds. Huprine-tacrine heterodimers are not neurotoxic to SHSY5Y cells at a range of concentrations from 1 to 0.001 μM, and some of them can protect cells from the oxidative damage produced by hydrogen peroxide at concentrations as low as 0.001 μM. Conclusion: Even though it remains to be determined if these compounds act as agonists at M 1 receptors, as it is the case of the parent huprine Y, their low nanomolar M 1 affinity and neuroprotective effects expand their multitarget profile and increase their interest as disease-modifying anti-Alzheimer agents. Copyright © 2012 S. Karger AG, Basel.
- Acetylcholinesterase inhibitor
- Hydrogen peroxide insult
- M agonist 1