Twelve novel conformationally constrained homologues of glutamic acid have been synthesized and pharmacologically characterized at ionotropic glutamate receptors (iGluRs). Synthesis of the target compounds involved 1,3-dipolar cycloaddition of nitrile oxides to suitable dipolarophiles. The structure to the compounds has been assigned by 1H NMR and, in the case of derivatives (±)-4a, (±)-4b, (±)-5a, and (±)-5b, by means of an X-ray crystallographic analysis carried out on intermediate (±)-12a. The synthesized amino acids were found to be without affinity (Ki/IC50 > 100 μM) for iGluRs with the exception of compounds (±)-4b and (±)-5b, which showed a modest affinity for NMDA receptors (Ki = 34 and 13 μM, respectively). The results indicate that the increased conformational constraints introduced by the cyclopropane ring and the spiro-attached proline ring are both detrimental to the pharmacological activity.

Synthesis and pharmacological evaluation of novel conformationally constrained homologues of glutamic acid / P. Conti, C. Antonio, A. Pinto, G. Roda, L. Tamborini, N. Birgitte, M. Ulf, F. Karla, A. Colombo, C. De Micheli. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 42:8(2007), pp. 1059-1068. [10.1016/j.ejmech.2007.01.013]

Synthesis and pharmacological evaluation of novel conformationally constrained homologues of glutamic acid

P. Conti
Primo
;
A. Pinto;G. Roda;L. Tamborini;A. Colombo
Penultimo
;
C. De Micheli
Ultimo
2007

Abstract

Twelve novel conformationally constrained homologues of glutamic acid have been synthesized and pharmacologically characterized at ionotropic glutamate receptors (iGluRs). Synthesis of the target compounds involved 1,3-dipolar cycloaddition of nitrile oxides to suitable dipolarophiles. The structure to the compounds has been assigned by 1H NMR and, in the case of derivatives (±)-4a, (±)-4b, (±)-5a, and (±)-5b, by means of an X-ray crystallographic analysis carried out on intermediate (±)-12a. The synthesized amino acids were found to be without affinity (Ki/IC50 > 100 μM) for iGluRs with the exception of compounds (±)-4b and (±)-5b, which showed a modest affinity for NMDA receptors (Ki = 34 and 13 μM, respectively). The results indicate that the increased conformational constraints introduced by the cyclopropane ring and the spiro-attached proline ring are both detrimental to the pharmacological activity.
Glutamic acid homologues; Ionotropic glutamate receptors; Isoxazoline derivatives; Spirocyclic compounds
Settore CHIM/08 - Chimica Farmaceutica
Article (author)
File in questo prodotto:
File Dimensione Formato  
European Journal of Med Chem 2007, 42, 1059-1068.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 399.3 kB
Formato Adobe PDF
399.3 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/35489
Citazioni
  • ???jsp.display-item.citation.pmc??? 1
  • Scopus 24
  • ???jsp.display-item.citation.isi??? 25
social impact