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

Abstract

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 δ-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.

• Authors: Nuno A L Pereira, Francesc X Sureda, Maria Pérez, Mercedes Amat, Maria M M Santos
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 21 Issue 8 (Aug 06 2016) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 27509489 (Publication Type: Journal Article)

Chemical References

• Indoles
• Quinolizidines
• Receptors, N-Methyl-D-Aspartate
• Small Molecule Libraries
• tryptophanol
• Tryptophan

Topics

• Cyclization
• Indoles (chemical synthesis, chemistry, pharmacology)
• Molecular Structure
• Quinolizidines (chemical synthesis, chemistry, pharmacology)
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors)
• Small Molecule Libraries (chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Tryptophan (analogs & derivatives, chemistry)