Synthesis, preliminary evaluation and molecular modeling studies of new, conformationally constrained analogues of the competitive NMDA receptor antagonist 4-(phosphonomethyl)-2-piperidinecarboxylic acid (CGS 19755).
Two new spirobicyclophosphonate isomers (19 and 20), conformationally constrained analogues of the potent competitive NMDA antagonist CGS 19755 (4), have been designed and synthetized with the aim of gaining insight into the conformational preference of the crucial distal phosphonate moiety at the antagonist NMDA binding site. The preliminary biological evaluation reveals that the activity as NMDA antagonist resides only in the (1R,5S,7R)-isomer (19), characterized by a (-)-gauche disposition around the C1-C5 bond, thus confirming previously reported pharmacophore models.
Pellicciari
R
R
Istituto di Chimica e Tecnologia del Farmaco, Università di Perugia, Italy.
Marinozzi
M
M
Natalini
B
B
Costantino
G
G
Lankin
D C
DC
Snyder
J P
JP
Monahan
J B
JB
D001665:Binding Sites; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D010875:Pipecolic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D018691:Excitatory Amino Acid Antagonists; D010875:Pipecolic Acids; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; C053672:selfotel