Synthesis and pharmacology of 3-hydroxy-delta2-isoxazoline-cyclopentane analogues of glutamic acid.
The synthesis and pharmacology of two potential glutamic acid receptor ligands are described. Preparation of the bicyclic 3-hydroxy-delta2-isoxazoline-cyclopentane derivatives (+/-)-7 and (+/-)-8 was accomplished via 1,3-dipolar cycloaddition of bromonitrile oxide to suitably protected 1-amino-cyclopent-3-enecarboxylic acids. Their structure was established using a combination of 1H NMR spectroscopy and molecular mechanics calculations carried out on the intermediate cycloadducts (+/-)-11 and (+/-)-12. Amino acid derivatives (+/-)-7 and (+/-)-8 were assayed at ionotropic and metabotropic glutamic acid receptor subtypes and their activity compared with that of trans-ACPD and cis-ACPD. The results show that the replacement of the omega-carboxylic group of the model compounds with the 3-hydroxy-delta2-isoxazoline moiety abolishes or reduces drastically the activity at the metabotropic glutamate receptors. Conversely, on passing from cis-ACPD to derivative (+/-)-8, the agonist activity at NMDA receptors is almost unaffected.
Conti
P
P
Istituto di Chimica Farmaceutica, Università di Milano, viale Abruzzi, 42, 20131 Milan, Italy. paola.conti@unimi.it
De Amici
M
M
Bräuner-Osborne
H
H
Madsen
U
U
Toma
L
L
De Micheli
C
C
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects; D003500:Cyclization; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D005971:Glutamates / Q000138:chemical synthesis* / Q000494:pharmacology*; D066298:In Vitro Techniques; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects; D017470:Receptors, Glutamate / Q000187:drug effects*; D018092:Kainic Acid Receptors / Q000187:drug effects; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D013237:Stereoisomerism; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D000596:Amino Acids; D003515:Cycloleucine; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D008024:Ligands; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; C036361:1-amino-1,3-dicarboxycyclopentane