title: 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: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. nalpereira@ff.ulisboa.pt.
authors: Nuno A L
authors: NA
authors: Pereira
authors: Pharmacology Unit, Faculty of Medicine and Health Sciences, Universitat Rovira i Virgili, C./St. Llorenç 21, 43201 Reus (Tarragona), Spain. francesc.sureda@urv.cat.
authors: Francesc X
authors: FX
authors: Sureda
authors: Laboratory of Organic Chemistry, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, s/n, 08028 Barcelona, Spain. mariaperez@ub.edu.
authors: Maria
authors: M
authors: Pérez
authors: Laboratory of Organic Chemistry, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, s/n, 08028 Barcelona, Spain. amat@ub.edu.
authors: Mercedes
authors: M
authors: Amat
authors: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. mariasantos@ff.ulisboa.pt.
authors: Maria M M
authors: MM
authors: Santos
mesh_terms: D003500:Cyclization; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D054837:Quinolizidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D014364:Tryptophan / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D007211:Indoles; D054837:Quinolizidines; D016194:Receptors, N-Methyl-D-Aspartate; D054852:Small Molecule Libraries; C069544:tryptophanol; D014364:Tryptophan
keywords: 1,2-aminoalcohols; NMDA receptor; antagonists; indoloquinolizidines; tryptophanol