Genetic Up-Regulation or Pharmacological Activation of the Na+/Ca2+ Exchanger 1 (NCX1) Enhances Hippocampal-Dependent Contextual and Spatial Learning and Memory

New Insights into the Structure–Activity Relationship and Neuroprotective Profile of Benzodiazepinone Derivatives of Neurounina-1 as Modulators of the Na+/Ca2+ Exchanger Isoforms

“…In particular, compound 14 was able to stimulate NCX1 and NCX3, whereas compound 1 resulted in a selective NCX1 activator, confirming previous results obtained by single-cell Fura-2-monitored Ca 2+ influx techniques. 27 …”

“…The formation of a six-membered intramolecular hydrogen bond between the protonated nitrogen of R and the carbonyl oxygen of the benzodiazepinone ring represented the driving force for the resulting conformational behavior ( Figure 7 A). Accordingly, the selectivity of compound 1 toward NCX1 27 compared to Neurounina-1 , which stimulates both NCX1 and NCX2, 25 is not due to conformational effects but to the steric hindrance introduced by the chlorine atom at the ortho position of the pendant phenyl ring, which is not tolerated by the NCX2 binding site ( Figure 8 D).…”

“…As evidenced by our 3-D SAR analysis, depending on the different linkers present in the structure, the R groups of Neurounina-1 and compounds 1 , 4 , and 14 assume different orientations with respect to the benzodiazepinone skeleton. Accordingly, we have (i) NCX1 activators as Neurounina-1 (equally potent on the reverse and forward modes) 25 and compound 1 (more effective on the reverse mode), 27 (ii) the NCX1 (reverse mode) inhibitor 4 , and (iii) the NCX1 (reverse mode) and NCX3 (forward mode) activator 14 ( Figure 8 ). According to the observed pharmacological profile, the NCX1 inhibitor 4 should select/induce the OF calcium-loaded occluded conformation of the transporter (i.e., working in the reverse mode; PDB: 5HXR, Figure S6 ).…”

Na+/Ca2+ exchanger isoform 1 takes part to the Ca2+-related prosurvival pathway of SOD1 in primary motor neurons exposed to beta-methylamino-L-alanine

“…Moreover, the relevance of NCX1 at motor neuron level was confirmed by the neuroprotective effect exerted by the new selective pharmacological activator of NCX1, CN-PYB2 (26), in L-BMAA-treated motor neurons. Furthermore, we showed that in SBFI-loaded motor neurons, SOD1 (400 ng/mL) as well as ApoSOD1 (400 ng/mL) induced a significant increase in [Na + ] i .…”

“…L-BMAA treatment and cell viability measurement. Primary cultures of motor neurons were exposed to 300 M L-BMAA for 48 h. SOD1 (400 ng/ml) or ApoSOD1 (400 ng/ml) were added in fresh medium 10 minutes before L-BMAA addition, while the specific NCX1 activator, CN-PYB2 (10 nM) (26), was added in fresh medium together with the neurotoxin. After 48 h exposure to L-BMAA, mitochondrial activity was evaluated by the MTT (3[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay.…”