Synthesis of conformationally constrained glutamic acid homologues and investigation of their pharmacological profiles.
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.
Conti
Paola
P
Istituto di Chimica Farmaceutica e Tossicologica Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy. paola.conti@unimi.it
Pinto
Andrea
A
Tamborini
Lucia
L
Grazioso
Giovanni
G
De Sarro
Giovambattista
G
Bräuner-Osborne
Hans
H
Szabo
Geza
G
Gábor Hársing
László
L
De Micheli
Carlo
C
D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D018698:Glutamic Acid / Q000138:chemical synthesis / Q000737:chemistry*; D051379:Mice; D008811:Mice, Inbred DBA; D008968:Molecular Conformation
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid