Atypical 1,4-dihydropyridine derivatives, an approach to neuroprotection and memory enhancement

This mini review is devoted to the design and pharmacological studies of novel atypical 1,4-dihydropyridine (DHP) derivatives which differ to a great extent from the traditional DHPs either by lack of neuronal calcium channel blocking activity and/or inability to protect mitochondrial processes. About 100 new DHP derivatives were screened and the mostly active were selected for detailed studies. The compounds of the series of the amino acid ("free" plus "crypto")-containing DHPs and lipophilic di-cyclic DHPs demonstrated long-lasting neuroprotective and/or memory-enhancing action, particularly at low doses (0.005-0.05mg/kg) in different neurodeficiency rat or mice models, and exerted neurotransmitter-modulating effects. The studies have shown an ability of these atypical DHPs to normalize the expression of neuronal proteins, which participate in the regulation of neurotransmission (particularly of the GABAergic system) and synaptic plasticity that has been impaired in animal models, including Alzheimer's disease transgenic mice. The obtained results indicate that the tested DHP compounds can be considered as candidate molecules either for their further chemical modifications or for the more detailed studies to identify cell targets essential for neuroprotection and memory enhancing.