Synthesis and biological evaluation of pro-drugs of GW196771, a potent glycine antagonist acting at the NMDA receptor

Farmaco (Societa chimica italiana : 1989) Pub Date : 2005-05-01 DOI:10.1016/j.farmac.2005.03.007

Angela Angusti , Elisa Durini , Silvia Vertuani , Alessandro Dalpiaz , A. Ruffo , Romano Di Fabio , Daniele Donati , Giorgio Pentassuglia , Giovanni Vitulli , Robert J. Barnaby , Stefano Manfredini

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引用次数: 1

Abstract

GW196771 is a potent antagonist of the modulatory glycine site of the N-methyl-d-aspartate (NMDA) receptor exhibiting outstanding in vivo profile in different animal models of chronic pain. With the aim to maximize the drug delivery to the target organs a suitable “pro-drug approach” was attempted; in this regards two conjugates of GW196771 with nutrients actively transported into the brain, namely adenosine and glucose, were prepared and investigated. These compounds, were evaluated in vitro in terms of their stability in rat plasma and in vivo on rats. Although an improvement was observed in terms of brain penetration of the esters vs. the parent compound, the amount of the latter did not increase significantly, probably due to some degradation events in the brain, different from the expected ester hydrolysis, resulting in a reduced availability of GW196771.

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作用于NMDA受体的强效甘氨酸拮抗剂GW196771前药的合成及生物学评价

GW196771是n -甲基-d-天冬氨酸(NMDA)受体调节甘氨酸位点的有效拮抗剂，在不同的慢性疼痛动物模型中表现出出色的体内特征。为了最大限度地将药物输送到靶器官，尝试了一种合适的“亲药方法”;为此，我们制备并研究了GW196771与主动转运到脑内的营养物质即腺苷和葡萄糖的两种缀合物。研究了这些化合物在体外和体内对大鼠血浆的稳定性。虽然与母体化合物相比，酯类化合物的脑渗透能力有所提高，但后者的数量并没有显著增加，这可能是由于脑内的一些降解事件，与预期的酯水解不同，导致GW196771的可用性降低。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Farmaco (Societa chimica italiana : 1989)

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