ABSTRACT
The support of a delicate reagent on a solid matrix allows for better and safer handling of the reagent itself. Because we had an interest in silicon-based supported reagents(1) we turned our attention to a polymer-supported trialkylsilyl cyanide and trialkylsilyl azide starting from a commercially available trialkylsilane resin. The supported cyanide was obtained with excellent yield and proved to be shelf-stable. This supported reagent was reacted with a series of aldehydes and ketones yielding the corresponding polymer-supported cyanohydrins in good-to-excellent yields. A stability study on a model cyanohydrin demonstrated that these supported intermediates also can be stored for a prolonged time. For the last step, a cleavage strategy that could release either cyanohydrins or alpha-hydroxy esters was adopted. Finally, we prepared a polymer-supported trialkylsilyl azide, which also proved to be shelf-stable.
Subject(s)
Aldehydes/chemistry , Ketones/chemistry , Nitriles/chemical synthesis , Polymers , Azides , Cyanides , Indicators and Reagents , Molecular Structure , Nitriles/chemistry , Spectrometry, Mass, Secondary IonABSTRACT
A series of indole-2-carboxylates bearing suitable chains at the C-3 position of the indole nucleus was synthesized and evaluated in terms of in vitro affinity using [3H]glycine binding assay and in vivo potency by inhibition of convulsions induced by N-methyl-D-aspartate (NMDA) in mice. 3-[2-[(Phenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2-carboxyl ic acid (8) was an antagonist at the strychnine-insensitive glycine binding site (noncompetitive inhibition of the binding of [3H]TCP, pA2 = 8.1) displaying nanomolar affinity for the glycine binding site (pKi = 8.5), coupled with high glutamate receptor selectivity (> 1000-fold relative to the affinity at the NMDA, AMPA, and kainate binding sites). This indole derivative inhibited convulsions induced by NMDA in mice, when administered by both iv and po routes (ED50 = 0.06 and 6 mg/kg, respectively). The effect of the substituents on the terminal phenyl ring of the C-3 side chain was investigated. QSAR analysis suggested that the pKi value decreases with lipophilicity and steric bulk of substituents and increases with the electron donor resonance effect of the groups present in the para position of the terminal phenyl ring. According to these results the terminal phenyl ring of the C-3 side chain should lie in a nonhydrophobic pocket of limited size, refining the proposed pharmacophore model of the glycine binding site associated with the NMDA receptor.
Subject(s)
Excitatory Amino Acid Antagonists/pharmacology , Glycine Agents/pharmacology , Glycine/antagonists & inhibitors , Indoles/pharmacology , Animals , Binding Sites , Binding, Competitive , Carboxylic Acids , Cerebral Cortex/drug effects , Excitatory Amino Acid Antagonists/chemical synthesis , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/metabolism , Glycine/metabolism , Glycine Agents/chemical synthesis , Glycine Agents/chemistry , Glycine Agents/metabolism , Indoles/chemical synthesis , Indoles/chemistry , Indoles/metabolism , Magnetic Resonance Spectroscopy , Mice , Molecular Structure , N-Methylaspartate/pharmacology , Rats , Receptors, Glutamate/metabolism , Structure-Activity Relationship , Strychnine/pharmacologyABSTRACT
2,3-Dihydro-6,7-dichloro-pyrido[2,3-b]pyrazine-8-oxide was synthesized and evaluated for in vitro/in vivo antagonistic activity at the strychnine insensitive glycine binding site on the NMDA receptor revealing it to be a useful tool to evaluate the effectiveness of glycine antagonists in vivo.
