Synthesis of conformationally constrained glutamic acid homologues and investigation of their pharmacological profiles

Paola Conti, Andrea Pinto, Lucia Tamborini, Giovanni Grazioso, Giovambattista De Sarro, Hans Bräuner-Osborne, Geza Szabo, L. Hársing, Carlo De Micheli

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Homologation of the glutamic acid chain together with conformational constraint is a commonly used strategy to achieve selectivity towards different types of glutamate receptors. We investigated the effects of a further increase in the distance between the amino acid moiety and the distal carboxylate group of model compounds (±)-1 and (±)-2 on their activity/selectivity profiles. We therefore synthesized new derivatives (±)-3-(±)-6, which are homologues of glutamic acid containing three additional carbon units. Moreover, because the potency of NMDA antagonists can be markedly increased by replacing the distal carboxylate with the bioisosteric phosphonate group, we also prepared the corresponding phosphonate derivatives (±)-7-(±)- 10. All new compounds were submitted to binding assays with iGluRs, and derivatives (±)-3-(±)-6 were also tested in second messenger assays at representative mGluR subtypes. All the applied structural modifications were detrimental to the interaction with NMDA receptors. Conversely, structural variation of the nonselective mGluR ligand (±)-2 led to derivative (±)-5, which behaved as a selective group I metabotropic receptor antagonist. Notably, upon i.c.v. administration in DBA/2 mice, amino acid (±)-5 produced a significant protection against audiogenic seizures, whereas it was inactive after i.p. administration.

Original languageEnglish
Pages (from-to)1639-1647
Number of pages9
JournalChemMedChem
Volume2
Issue number11
DOIs
Publication statusPublished - Nov 12 2007

Fingerprint

Organophosphonates
Glutamic Acid
Pharmacology
Derivatives
Amino Acids
Inbred DBA Mouse
Glutamate Receptors
Second Messenger Systems
N-Methylaspartate
N-Methyl-D-Aspartate Receptors
Assays
Seizures
Carbon
Ligands

Keywords

  • Amino acids
  • Anticonvulsants
  • Glutamic acid
  • mGluR antagonists
  • NMDA receptors

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this

Conti, P., Pinto, A., Tamborini, L., Grazioso, G., De Sarro, G., Bräuner-Osborne, H., ... De Micheli, C. (2007). Synthesis of conformationally constrained glutamic acid homologues and investigation of their pharmacological profiles. ChemMedChem, 2(11), 1639-1647. https://doi.org/10.1002/cmdc.200700118

Synthesis of conformationally constrained glutamic acid homologues and investigation of their pharmacological profiles. / Conti, Paola; Pinto, Andrea; Tamborini, Lucia; Grazioso, Giovanni; De Sarro, Giovambattista; Bräuner-Osborne, Hans; Szabo, Geza; Hársing, L.; De Micheli, Carlo.

In: ChemMedChem, Vol. 2, No. 11, 12.11.2007, p. 1639-1647.

Research output: Contribution to journalArticle

Conti, P, Pinto, A, Tamborini, L, Grazioso, G, De Sarro, G, Bräuner-Osborne, H, Szabo, G, Hársing, L & De Micheli, C 2007, 'Synthesis of conformationally constrained glutamic acid homologues and investigation of their pharmacological profiles', ChemMedChem, vol. 2, no. 11, pp. 1639-1647. https://doi.org/10.1002/cmdc.200700118
Conti P, Pinto A, Tamborini L, Grazioso G, De Sarro G, Bräuner-Osborne H et al. Synthesis of conformationally constrained glutamic acid homologues and investigation of their pharmacological profiles. ChemMedChem. 2007 Nov 12;2(11):1639-1647. https://doi.org/10.1002/cmdc.200700118
Conti, Paola ; Pinto, Andrea ; Tamborini, Lucia ; Grazioso, Giovanni ; De Sarro, Giovambattista ; Bräuner-Osborne, Hans ; Szabo, Geza ; Hársing, L. ; De Micheli, Carlo. / Synthesis of conformationally constrained glutamic acid homologues and investigation of their pharmacological profiles. In: ChemMedChem. 2007 ; Vol. 2, No. 11. pp. 1639-1647.
@article{163a9911f57b453482108a7b406f1a40,
title = "Synthesis of conformationally constrained glutamic acid homologues and investigation of their pharmacological profiles",
abstract = "Homologation of the glutamic acid chain together with conformational constraint is a commonly used strategy to achieve selectivity towards different types of glutamate receptors. We investigated the effects of a further increase in the distance between the amino acid moiety and the distal carboxylate group of model compounds (±)-1 and (±)-2 on their activity/selectivity profiles. We therefore synthesized new derivatives (±)-3-(±)-6, which are homologues of glutamic acid containing three additional carbon units. Moreover, because the potency of NMDA antagonists can be markedly increased by replacing the distal carboxylate with the bioisosteric phosphonate group, we also prepared the corresponding phosphonate derivatives (±)-7-(±)- 10. All new compounds were submitted to binding assays with iGluRs, and derivatives (±)-3-(±)-6 were also tested in second messenger assays at representative mGluR subtypes. All the applied structural modifications were detrimental to the interaction with NMDA receptors. Conversely, structural variation of the nonselective mGluR ligand (±)-2 led to derivative (±)-5, which behaved as a selective group I metabotropic receptor antagonist. Notably, upon i.c.v. administration in DBA/2 mice, amino acid (±)-5 produced a significant protection against audiogenic seizures, whereas it was inactive after i.p. administration.",
keywords = "Amino acids, Anticonvulsants, Glutamic acid, mGluR antagonists, NMDA receptors",
author = "Paola Conti and Andrea Pinto and Lucia Tamborini and Giovanni Grazioso and {De Sarro}, Giovambattista and Hans Br{\"a}uner-Osborne and Geza Szabo and L. H{\'a}rsing and {De Micheli}, Carlo",
year = "2007",
month = "11",
day = "12",
doi = "10.1002/cmdc.200700118",
language = "English",
volume = "2",
pages = "1639--1647",
journal = "ChemMedChem",
issn = "1860-7179",
publisher = "John Wiley and Sons Ltd",
number = "11",

}

TY - JOUR

T1 - Synthesis of conformationally constrained glutamic acid homologues and investigation of their pharmacological profiles

AU - Conti, Paola

AU - Pinto, Andrea

AU - Tamborini, Lucia

AU - Grazioso, Giovanni

AU - De Sarro, Giovambattista

AU - Bräuner-Osborne, Hans

AU - Szabo, Geza

AU - Hársing, L.

AU - De Micheli, Carlo

PY - 2007/11/12

Y1 - 2007/11/12

N2 - Homologation of the glutamic acid chain together with conformational constraint is a commonly used strategy to achieve selectivity towards different types of glutamate receptors. We investigated the effects of a further increase in the distance between the amino acid moiety and the distal carboxylate group of model compounds (±)-1 and (±)-2 on their activity/selectivity profiles. We therefore synthesized new derivatives (±)-3-(±)-6, which are homologues of glutamic acid containing three additional carbon units. Moreover, because the potency of NMDA antagonists can be markedly increased by replacing the distal carboxylate with the bioisosteric phosphonate group, we also prepared the corresponding phosphonate derivatives (±)-7-(±)- 10. All new compounds were submitted to binding assays with iGluRs, and derivatives (±)-3-(±)-6 were also tested in second messenger assays at representative mGluR subtypes. All the applied structural modifications were detrimental to the interaction with NMDA receptors. Conversely, structural variation of the nonselective mGluR ligand (±)-2 led to derivative (±)-5, which behaved as a selective group I metabotropic receptor antagonist. Notably, upon i.c.v. administration in DBA/2 mice, amino acid (±)-5 produced a significant protection against audiogenic seizures, whereas it was inactive after i.p. administration.

AB - Homologation of the glutamic acid chain together with conformational constraint is a commonly used strategy to achieve selectivity towards different types of glutamate receptors. We investigated the effects of a further increase in the distance between the amino acid moiety and the distal carboxylate group of model compounds (±)-1 and (±)-2 on their activity/selectivity profiles. We therefore synthesized new derivatives (±)-3-(±)-6, which are homologues of glutamic acid containing three additional carbon units. Moreover, because the potency of NMDA antagonists can be markedly increased by replacing the distal carboxylate with the bioisosteric phosphonate group, we also prepared the corresponding phosphonate derivatives (±)-7-(±)- 10. All new compounds were submitted to binding assays with iGluRs, and derivatives (±)-3-(±)-6 were also tested in second messenger assays at representative mGluR subtypes. All the applied structural modifications were detrimental to the interaction with NMDA receptors. Conversely, structural variation of the nonselective mGluR ligand (±)-2 led to derivative (±)-5, which behaved as a selective group I metabotropic receptor antagonist. Notably, upon i.c.v. administration in DBA/2 mice, amino acid (±)-5 produced a significant protection against audiogenic seizures, whereas it was inactive after i.p. administration.

KW - Amino acids

KW - Anticonvulsants

KW - Glutamic acid

KW - mGluR antagonists

KW - NMDA receptors

UR - http://www.scopus.com/inward/record.url?scp=49649123564&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=49649123564&partnerID=8YFLogxK

U2 - 10.1002/cmdc.200700118

DO - 10.1002/cmdc.200700118

M3 - Article

C2 - 17849399

AN - SCOPUS:49649123564

VL - 2

SP - 1639

EP - 1647

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

IS - 11

ER -