Synthesis of novel pyrrolo[3,4-d]pyrazole-dicarboxylic acids and evaluation of their interaction with glutamate receptors.
Chiral pyrazoline amino acids (3aR,4S,6aR)-1a and (3aR,4S,6aR)-1b, and (3aS,6S,6aS)-2a and (3aS,6S,6aS)-2b, which are conformationally constrained analogues of glutamic and homoglutamic acid, respectively, were prepared via a strategy based on the 1,3-dipolar cycloaddition of a nitrile imine to methyl N-Boc-3,4-didehydro-(S)-prolinate. The new 'amino acids' were tested for activity at ionotropic glutamate receptors. Solely the derivative (3aR,4S,6aR)-1a, which is structurally related to the previously described 4,5-dihydroisoxazole analogue (S)-CIP-A, turned out to be a potent and selective agonist for the AMPA receptors. The biological activity is due to the interaction with the orthosteric glutamate binding site.
Conti
Paola
P
Istituto di Chimica Farmaceutica e Tossicologica Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, I-20133 Milano. paola.conti@unimi.it
di Ventimiglia
Samuele Joppolo
SJ
Pinto
Andrea
A
Tamborini
Lucia
L
Menniti
Frank S
FS
Lazzaro
John T
JT
De Micheli
Carlo
C
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003998:Dicarboxylic Acids / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D013237:Stereoisomerism
D003998:Dicarboxylic Acids; D011720:Pyrazoles; D018091:Receptors, AMPA; D002118:Calcium