Synthesis and pharmacological evaluation of novel conformationally constrained homologues of glutamic acid.
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 (1)H 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 (K(i)/IC(50)>100microM) for iGluRs with the exception of compounds (+/-)-4b and (+/-)-5b, which showed a modest affinity for NMDA receptors (K(i)=34 and 13microM, 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.
Conti
Paola
P
Istituto di Chimica Farmaceutica e Tossicologica "Pietro Pratesi", Università degli Studi di Milano, Viale Abruzzi 42, 20131 Milano, Italy.
Caligiuri
Antonio
A
Pinto
Andrea
A
Roda
Gabriella
G
Tamborini
Lucia
L
Nielsen
Birgitte
B
Madsen
Ulf
U
Frydenvang
Karla
K
Colombo
Alessio
A
De Micheli
Carlo
C
D018360:Crystallography, X-Ray; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D011485:Protein Binding; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013329:Structure-Activity Relationship
D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid