Synthesis of a new series of N-hydroxy, N-alkylamides of aminoacids as ligands of NMDA glycine site

• Published in: European journal of medicinal chemistry Vol. 34; no. 9; pp. 711 - 717
• Main Authors: Ghidini, Eleonora, Delcanale, Maurizio, Servadio, Vittorino, Pietra, Claudio, Bergamaschi, Marco, Villetti, Gino, Redenti, Enrico, Ventura, Paolo, Merlini, Lucio
• Format: Journal Article
• Language: English
• Published: PARIS CEDEX 15 Elsevier Masson SAS 01.09.1999; Elsevier
• Subjects: aminoacids; Biological and medical sciences; Chemistry, Medicinal; Glutamatergic system (aspartate and other excitatory aminoacids); glycine antagonists; hydroxamic acids; Life Sciences & Biomedicine; Medical sciences; N-hydroxyamides of aminoacids; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; N-hydroxyamides of aminoacids; glycine antagonists; hydroxamic acids; aminoacids; GUINEA-PIG ILEUM; D-ASPARTATE RECEPTOR; AGONISTS; ATOMIC PHYSICOCHEMICAL PARAMETERS; AFFINITY; PHARMACOLOGY; RAT-BRAIN; ANTAGONISTS; BINDING; DIRECTED QUANTITATIVE STRUCTURE; Rat; Aliphatic compound; Rodentia; Central nervous system; Hydroxamic acid; Glutamate receptor; In vitro; α-Aminoacid; Vertebrata; Biological fixation; Mammalia; Structure activity relation; Animal; Glycine receptor; Benzenic compound; NMDA receptor; Chemical synthesis; Brain (vertebrata)
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/S0223-5234(99)00222-6

Anew series of N-hydroxy, N-alkylamides of aminoacids structurally related to the N-hydroxy-3-amino-2 pyrrolidone [(±)HA-966] was synthesised and evaluated for the ability to displace [ 3H]Glycine, [ 3H]CGS19755, [ 3H]AMPA and [ 3H]Kainate binding sites. The N-heptyl glycinamide 5a was the most potent compound (IC 50 = 4.5 μM) in inhibiting [ 3H]Glycine binding. Compounds 5b, 5d, 5m, 5p, 5q and 5r showed an activity similar to (±)HA-966, whereas 5h, 5i, 5n and 5s appeared less active. None of the compounds tested exhibited a significant displacement of [ 3H]AMPA and [ 3H]Kainate binding sites. Compounds active in the [ 3H]Glycine binding inhibited, to a different degree, NMDA induced contractions in guinea-pig LMPP preparation.