Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists

Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool), and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the syntheses of natural products or biological active molecules containing the aminoalcohol functionality. In this communication, we report the development of a small library of indolo[2,3-a]quinolizidines and evaluation of their activity as N-Methyl D-Aspartate (NMDA) receptor antagonists. The indolo[2,3-a]quinolizidine scaffold was obtained using the following key steps: (i) a stereoselective cyclocondensation of (S)- or (R)-tryptophanol with appropriate racemic -oxoesters; (ii) a stereocontrolled cyclization on the indole nucleus. The synthesized enantiopure indolo[2,3-a]quinolizidines were evaluated as NMDA receptor antagonists and one compound was identified to be 2.9-fold more potent as NMDA receptor blocker than amantadine (used in the clinic for Parkinson's disease). This compound represents a hit compound for the development of novel NMDA receptor antagonists with potential applications in neurodegenerative disorders associated with overactivation of NMDA receptors

Tryptophanol-derived oxazolopiperidone lactams: identification of a hit compound as NMDA receptor antagonist

N-Methyl-D-Aspartate (NMDA) receptors are neuronal ionotropic channels that play an important role in memory and learning processes. Their exacerbated activation leads to neuron death by necrosis or apoptosis in a phenomenon called excitotoxicity. Compounds like memantine or amantadine act as antagonists of these receptors and are currently used for the treatment of Alzheimer's or Parkinson's diseases. We herein present the development of a series of new NMDA receptor antagonists using enantiopure tryptophanol and racemic δ-oxo-esters as synthetic precursors in only one synthetic step and good yields. The most active hit exhibited an IC50 of 63.4 µM in cultured rat cerebellar granule neurons thus being 1.5 fold more active than the positive control used, amantadine (IC50 = 92 µM). The versatility of our synthetic approach together with the well-defined absolute stereoutcome of the tryptophanol-derived oxazolopiperidones is currently being explored to produce valuable structure activity relationships for the development of new potent NMDAR antagonists

Synthesis of phenylalaninol-derived oxazolopyrrolidone lactams and evaluation as NMDA receptor antagonists

N-Methyl-D-aspartate (NMDA) receptor antagonists are known to rescue neuronal cell death caused by excessive activation of glutamate receptors. This phenomenon, known as excitotoxicity, is implicated in the pathogenesis of several neurodegenerative disorders including ischemia, Alzheimer's disease, Parkinson's disease, and Huntington's disease. Unfortunately, some NMDA receptor antagonists have shown discouraging results when tested in clinical trials. However, recent advances in the physiology and pharmacology of the NMDA receptor have kept interest alive in modulating NMDA receptors for therapeutic intervention. We present here the synthesis of a small library of phenylalaninol-derived oxazolopyrrolidone lactams and their evaluation as NMDA receptor antagonists. The compounds were easily synthesized in yields up to 92 %. In addition, one of the compounds has a 50 % inhibitory concentration (IC 50) of 62 μM and offers potential to develop more potent NMDA receptor antagonists

Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists

Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool), and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the syntheses of natural products or biological active molecules containing the aminoalcohol functionality. In this communication, we report the development of a small library of indolo[2,3-a]quinolizidines and evaluation of their activity as N-Methyl D-Aspartate (NMDA) receptor antagonists. The indolo[2,3-a]quinolizidine scaffold was obtained using the following key steps: (i) a stereoselective cyclocondensation of (S)- or (R)-tryptophanol with appropriate racemic -oxoesters; (ii) a stereocontrolled cyclization on the indole nucleus. The synthesized enantiopure indolo[2,3-a]quinolizidines were evaluated as NMDA receptor antagonists and one compound was identified to be 2.9-fold more potent as NMDA receptor blocker than amantadine (used in the clinic for Parkinson's disease). This compound represents a hit compound for the development of novel NMDA receptor antagonists with potential applications in neurodegenerative disorders associated with overactivation of NMDA receptors

Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists

Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool), and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the syntheses of natural products or biological active molecules containing the aminoalcohol functionality. In this communication, we report the development of a small library of indolo[2,3-a]quinolizidines and evaluation of their activity as N-Methyl D-Aspartate (NMDA) receptor antagonists. The indolo[2,3-a]quinolizidine scaffold was obtained using the following key steps: (i) a stereoselective cyclocondensation of (S)- or (R)-tryptophanol with appropriate racemic -oxoesters; (ii) a stereocontrolled cyclization on the indole nucleus. The synthesized enantiopure indolo[2,3-a]quinolizidines were evaluated as NMDA receptor antagonists and one compound was identified to be 2.9-fold more potent as NMDA receptor blocker than amantadine (used in the clinic for Parkinson's disease). This compound represents a hit compound for the development of novel NMDA receptor antagonists with potential applications in neurodegenerative disorders associated with overactivation of NMDA receptors

Tryptophanol-derived oxazolopiperidone lactams: identification of a hit compound as NMDA receptor antagonist

N-Methyl-D-Aspartate (NMDA) receptors are neuronal ionotropic channels that play an important role in memory and learning processes. Their exacerbated activation leads to neuron death by necrosis or apoptosis in a phenomenon called excitotoxicity. Compounds like memantine or amantadine act as antagonists of these receptors and are currently used for the treatment of Alzheimer's or Parkinson's diseases. We herein present the development of a series of new NMDA receptor antagonists using enantiopure tryptophanol and racemic δ-oxo-esters as synthetic precursors in only one synthetic step and good yields. The most active hit exhibited an IC50 of 63.4 µM in cultured rat cerebellar granule neurons thus being 1.5 fold more active than the positive control used, amantadine (IC50 = 92 µM). The versatility of our synthetic approach together with the well-defined absolute stereoutcome of the tryptophanol-derived oxazolopiperidones is currently being explored to produce valuable structure activity relationships for the development of new potent NMDAR antagonists

Tryptophanol-derived oxazolopiperidone lactams: identification of a hit compound as NMDA receptor antagonist

N-Methyl-D-Aspartate (NMDA) receptors are neuronal ionotropic channels that play an important role in memory and learning processes. Their exacerbated activation leads to neuron death by necrosis or apoptosis in a phenomenon called excitotoxicity. Compounds like memantine or amantadine act as antagonists of these receptors and are currently used for the treatment of Alzheimer's or Parkinson's diseases. We herein present the development of a series of new NMDA receptor antagonists using enantiopure tryptophanol and racemic δ-oxo-esters as synthetic precursors in only one synthetic step and good yields. The most active hit exhibited an IC50 of 63.4 µM in cultured rat cerebellar granule neurons thus being 1.5 fold more active than the positive control used, amantadine (IC50 = 92 µM). The versatility of our synthetic approach together with the well-defined absolute stereoutcome of the tryptophanol-derived oxazolopiperidones is currently being explored to produce valuable structure activity relationships for the development of new potent NMDAR antagonists