NMDA receptors are glutamate-gated cation channels with high calcium permeability that play important roles in many aspects of the biology of higher organisms. They are critical for the development of the central nervous system (CNS), generation of rhythms for breathing and locomotion, and the processes underlying learning, memory, and neuroplasticity. Therefore, NMDA receptors are important therapeutic targets for many CNS disorders [1]. To date, clinically drugs targeting the PCP binding site of NMDA receptors have had only limited success due to poor efficacy and unacceptable side effects, including hallucinations, catatonia, ataxia, nightmares, and memory deficits [2]. Recently, it has been demonstrated that the piperidine ring of the potent PCP antagonists dexoxadrol and etoxadrol are not necessary for high NMDA receptor affinity since its replacement with aminomethyl or methylaminomethyl chains led to potent NMDA receptor antagonists [3]. Ring and side chain homologues of aminomethyl analogues of dexoxadrol and etoxadrol resulted in compounds showing high NMDA receptor affinity. The derivative 1 behaved as the most potent NMDA antagonist with an affinity value similar to those of dexoxadrol and etoxadrol, [3]. In the present work a series of regioisomers of 1, bearing the 1,4-dioxane nucleus, were prepared. The biological profiles of the novel compounds were assessed using binding assays at PCP binding site of the NMDA receptor. The functional activity of the most affine compounds 2-4 was investigated on L(tk-)-cells stably expressing the NMDA receptor subunits GluN1a and GluN2A by inhibition of the citotoxicity induced by the activation of NMDA receptors with (S)-glutamate and glycine. Compound 3, showing binding affinity and functional activity not significantly different from those of (S)-(+)-ketamine, displayed a promising therapeutic potential. Moreover, it also showed a cytotoxic activity significantly higher than that of (S)-(+)-ketamine on MCF7 human breast cancer cell lines, expressing NMDA receptors.
Novel 1,4-dioxane derivatives as NMDA receptor channel blockers
DEL BELLO, FABIO;BONIFAZI, ALESSANDRO;QUAGLIA, Wilma;PIERGENTILI, Alessandro;GIANNELLA, Mario;PIGINI, Maria;MAMMOLI, VALERIO;GIORGIONI, Gianfabio;CIMARELLI, Cristina;PELLEI, Maura;
2014-01-01
Abstract
NMDA receptors are glutamate-gated cation channels with high calcium permeability that play important roles in many aspects of the biology of higher organisms. They are critical for the development of the central nervous system (CNS), generation of rhythms for breathing and locomotion, and the processes underlying learning, memory, and neuroplasticity. Therefore, NMDA receptors are important therapeutic targets for many CNS disorders [1]. To date, clinically drugs targeting the PCP binding site of NMDA receptors have had only limited success due to poor efficacy and unacceptable side effects, including hallucinations, catatonia, ataxia, nightmares, and memory deficits [2]. Recently, it has been demonstrated that the piperidine ring of the potent PCP antagonists dexoxadrol and etoxadrol are not necessary for high NMDA receptor affinity since its replacement with aminomethyl or methylaminomethyl chains led to potent NMDA receptor antagonists [3]. Ring and side chain homologues of aminomethyl analogues of dexoxadrol and etoxadrol resulted in compounds showing high NMDA receptor affinity. The derivative 1 behaved as the most potent NMDA antagonist with an affinity value similar to those of dexoxadrol and etoxadrol, [3]. In the present work a series of regioisomers of 1, bearing the 1,4-dioxane nucleus, were prepared. The biological profiles of the novel compounds were assessed using binding assays at PCP binding site of the NMDA receptor. The functional activity of the most affine compounds 2-4 was investigated on L(tk-)-cells stably expressing the NMDA receptor subunits GluN1a and GluN2A by inhibition of the citotoxicity induced by the activation of NMDA receptors with (S)-glutamate and glycine. Compound 3, showing binding affinity and functional activity not significantly different from those of (S)-(+)-ketamine, displayed a promising therapeutic potential. Moreover, it also showed a cytotoxic activity significantly higher than that of (S)-(+)-ketamine on MCF7 human breast cancer cell lines, expressing NMDA receptors.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
