135335-16-9Relevant academic research and scientific papers
N-SUBSTITUTED ALPHA-AMINO ACIDS AND DERIVATIVES THEREOF HAVING PHARMACEUTICAL ACTIVITY
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, (2008/06/13)
N-substituted α-amino acids and derivatives thereof are described, as well as methods for the preparation and pharmaceutical composition of same, which are useful in selectively blocking the N-methyl-D-aspartate (NMDA) excitatory amino acid receptors in m
Exploration of N-Phosphonoalkyl-, N-Phosphonoalkenyl-, and N-(Phosphonoalkyl)phenyl-Spaced α-Amino Acids as Competitive N-Methyl-D-aspartic Acid Antagonists
Bigge, Christopher F.,Johnson, Graham,Ortwine, Daniel F.,Drummond, James T.,Retz, Daniel M.,et al.
, p. 1371 - 1384 (2007/10/02)
A series of N-substituted α-amino acids containing terminal phosphonic acid groups has been synthesized as potential N-methyl-D-aspartate (NMDA) receptor antagonists.NMDA receptor affinity was determined by displacement of a known ligand (CPP) from crude rat brain synaptic membranes; an antagonists action was demonstrated by the inhibition of glutamate-induced accumulation of (45Ca2+> in cultured rat cortical neurons.Receptor affinity was significantly correlated with antagonist activity (Figure 1).Moderate affinity (IC50 = 1-2 μM) was retained for analogues (31 and 32, Table I; and 59 and 66, Table II) with reduced flexibility in their phosphonate side chains and is consistent with entropy playing a role in determining receptor affinity.Modeling studies suggest a folded conformation that brings the distal phosphonic acid group into close proximity with the α-carboxylate is required for binding.Each of the active analogues possess entropy-limiting features (double bonds, phenyl rings) in their side chains that allows the superposition of their key NH2, α-COOH, and distal PO3H2 groups with those of known competitive antagonists.Affinity decreased for analogues with α-carbon substitution, presumably because the α-substituent inhibits the folding of these structures into a bioactive conformation and occupies receptor-excluded volume.A complete description of the NMDA antagonist pharmacophore model is provided in a companion paper.
Generation of N-Methyl-D-aspartate Agonist and Competitive Antagonist Pharmacophore Models. Design and Synthesis of Phosphonoalkyl-Substituted Tetrahydroisoquinolines as Novel Antagonists
Ortwine, Daniel F.,Malone, Thomas C.,Bigge, Christopher F.,Drummond, James T.,Humblet, Christine,et al.
, p. 1345 - 1370 (2007/10/02)
The preparation and binding affinity of a series of tetrahydroisoquinoline carboxylic acids at the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor is described, together with a molecular modeling analysis of NMDA agonists and antagonists.Usi
Substituted carboxytetrahydroisoquinolines and derivatives thereof having pharmaceutical activity
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, (2008/06/13)
The invention includes a novel series of substituted aryl or heteroaryl fused 2- or 6-carboxy piperidines and derivatives thereof which are useful in the treatment of cerebrovascular disorders, epilepsy, Huntington's disease, or as anesthetics particularly in surgical processes where a finite risk of cerebrovascular damage exists. Processes for making the compounds, novel intermediates useful in the processes, methods for using, and compositions containing the compounds are also included.
