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.

β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer’s Disease Therapy

“…Another rigidification strategy leading to βcarbolines was initiated after the identification of hit compounds presenting a biological activity on NMDA receptor and displaying both bicyclic lactam and indole moieties. 108 The study focused on nine β-carbolines, varying over their stereochemistry, substitution pattern and lactam-ring size, but the best obtained activity (compound 83, IC 50 = 30 μM) remained modest.…”

“…The two wings of the ‘V’ are formed by the tetrahydro-β-carboline core and the benzyl group, which interact in a similar manner than memantine or dizocilpine, i.e., with hydrophobic residues Val640, Leu643, and Ala644 (NR2A) or Met641, Val644, and Ala645 (NR1). Another rigidification strategy leading to β-carbolines was initiated after the identification of hit compounds presenting a biological activity on NMDA receptor and displaying both bicyclic lactam and indole moieties . The study focused on nine β-carbolines, varying over their stereochemistry, substitution pattern and lactam-ring size, but the best obtained activity (compound 83 , IC 50 = 30 μM) remained modest.…”