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Molecules 2016, 21(8), 1027; doi:10.3390/molecules21081027

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

1
Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
2
Pharmacology Unit, Faculty of Medicine and Health Sciences, Universitat Rovira i Virgili, C./St. Llorenç 21, 43201 Reus (Tarragona), Spain
3
Laboratory of Organic Chemistry, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, s/n, 08028 Barcelona, Spain
*
Author to whom correspondence should be addressed.
Academic Editors: Carlo Siciliano and Constantinos M. Athanassopoulos
Received: 31 May 2016 / Revised: 31 July 2016 / Accepted: 2 August 2016 / Published: 6 August 2016
(This article belongs to the Special Issue Synthesis of Bioactive Compounds from the Chiral Pool)
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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. View Full-Text
Keywords: indoloquinolizidines; 1,2-aminoalcohols; tryptophanol; NMDA receptor; antagonists indoloquinolizidines; 1,2-aminoalcohols; tryptophanol; NMDA receptor; antagonists
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MDPI and ACS Style

Pereira, N.A.L.; Sureda, F.X.; Pérez, M.; Amat, M.; Santos, M.M.M. Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists. Molecules 2016, 21, 1027.

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