Evaluation and synthesis of amino-hydroxy isoxazoles and pyrazoles as potential glycine agonists

Abstract

Except for structurally similar small amino acids, such as alanine, beta-alanine, and serine, compounds acting as glycine-receptor agonists are an unknown class of pharmacological agents. To investigate the potential of small, substituted heterocycles to act as glycine agonists, we have evaluated the similarities between glycine and a series of hydroxy- and amino-substituted pyrazoles and isoxazoles through complementary molecular modeling techniques. Using a "scorecard approach" to determine the overall similarity of projected agonist structures to glycine, we prioritized synthesis and subsequently prepared several novel derivatives. The biological activity of these compounds was compared to that of glycine by using a [3H]strychnine-mediated glycine receptor binding assay. Despite the close similarity in the calculated parameters when compared to glycine, no significant receptor-binding activity was observed for the targeted analogues. These results illustrate the structurally exacting nature of the glycine receptor.

A Facile One Step Synthesis of 3-(3-Μετηυl-Ιsoχαζolo[4,5-B] Pyridin-N-Oxide-6-Yl)chromen-2-Ones and Their Deoxygenation

“…The reaction of 3,5-dimethyl-4-nitro isoxazole 1 with 3-acetyl-2-oxo-2//-3-chromene 2 in presence of piperidine afforded 3-(3-methyl-isoxazolo [4,[5][6]pyridin-A-oxide-6-yl)-chromen-2-one 3 in a single step. The reaction of 3,5-dimethyl-4-nitro isoxazole 1 with 3-acetyl-2-oxo-2//-3-chromene 2 in presence of piperidine afforded 3-(3-methyl-isoxazolo [4,[5][6]pyridin-A-oxide-6-yl)-chromen-2-one 3 in a single step.…”

“…Different ring closure approaches for the preparation of the isoxazolo [4,[5][6]pyridine system have been studied from suitably substituted 4-aminoisoxazoles 1 ' 2 , ortho-difunctionalized pyridine derivatives 3,4 and 3,5-dimethyl-4-nitroisoxazole [5][6] . We have reported the synthesis of isoxazolo [4,5-b]pyridine-N-oxides by condensation-cyclisation processes of 3,5-dimethyl-4-nitro-isoxazole with the ß-dicarbonyl compounds in one step reaction 78 .…”

“…Pyridine-A-oxides on deoxygenation gives corresponding pyridines. As a sequel to our work on development of new methodologies for the synthesis of different substituted isoxazolo- [4,[5][6]pyridines, we herein report the synthesis of new chromene substituted isoxazolo [4,5-£]pyridines by a shortest route. As a sequel to our work on development of new methodologies for the synthesis of different substituted isoxazolo- [4,[5][6]pyridines, we herein report the synthesis of new chromene substituted isoxazolo [4,5-£]pyridines by a shortest route.…”

The Inhibitory Neural Circuitry as Target of Antiepileptic Drugs

“…Consequently, substitution of larger moieties, e.g. pyrazoles or aminohydroxyisoxazoles, to the glycine molecule results in a loss of GlycR agonistic action [126]. More recently, a number of glycinamide derivatives (Fig.…”

Synthesis of regioisomeric 2,5‐bis‐substituted‐aza‐benzothiopyranoindazoles

“…The extracts were washed with water (2 x 100 ml), dried over magnesium sulfate and concentrated to dryness. The white crystalline solid was collected by filtration to yield 35 (1.7 g, 77%), mp 73-74°; lit mp 70-73° [14]; 1 H nmr (deuteriochloroform): δ 8.23 (dd,J = 1.1,2.9 Hz,1H),2H),4.01 (s,3H).…”