Synthesis of novel N1-substituted bicyclic pyrazole amino acids and evaluation of their interaction with glutamate receptors.
N1-substituted bicyclic pyrazole amino acids (S)-9a-9c and (R)-9a-9c, which are conformationally constrained analogues of glutamic acid, were prepared via a strategy based on a 1,3-dipolar cycloaddition. The new amino acids were tested for activity at ionotropic and metabotropic glutamate receptors. Some of them turned out to be selective for the NMDA receptors, where they behaved as weak antagonists. The biological activity is mainly due to the interaction with the glutamate binding site, and not with the glycine co-agonist site.
Conti
Paola
P
Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Milano, Viale Abruzzi 42, I-20131 Milano. paola.conti@unimi.it
Grazioso
Giovanni
G
di Ventimiglia
Samuele Joppolo
SJ
Pinto
Andrea
A
Roda
Gabriella
G
Madsen
Ulf
U
Bräuner-Osborne
Hans
H
Nielsen
Birgitte
B
Costagli
Chiara
C
Galli
Alessandro
A
D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000138:chemical synthesis / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000378:metabolism; D015394:Molecular Structure; D017470:Receptors, Glutamate / Q000737:chemistry / Q000378:metabolism*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate