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Molecules 2016, 21(8), 1027;

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

Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
Pharmacology Unit, Faculty of Medicine and Health Sciences, Universitat Rovira i Virgili, C./St. Llorenç 21, 43201 Reus (Tarragona), Spain
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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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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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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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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