工程化甘丙肽类似物，可区分 GalR1 和 GalR2 受体亚型，并在全身给药后表现出抗惊厥活性。
Engineering galanin analogues that discriminate between GalR1 and GalR2 receptor subtypes and exhibit anticonvulsant activity following systemic delivery.
机构信息
Department of Medicinal Chemistry, College of Pharmacy, University of Utah, 421 WakaraWay, Salt Lake City, Utah 84108, USA.
出版信息
J Med Chem. 2010 Feb 25;53(4):1871-5. doi: 10.1021/jm9018349.
Abstract
Galanin modulates seizures in the brain through two galanin receptor subtypes, GalR1 and GalR2. To generate systemically active galanin receptor ligands that discriminate between GalR1 and GalR2, the GalR1-preferring analogue Gal-B2 (or NAX 5055) was rationally redesigned to yield GalR2-preferring analogues. Systematic truncations of the N-terminal backbone led to [N-Me,des-Sar]Gal-B2, containing N-methyltryptophan. This analogue exhibited 18-fold preference in binding toward GalR2, maintained agonist activity, and exhibited potent anticonvulsant activity in mice following intraperitoneal administration.
摘要
甘丙肽通过两种甘丙肽受体亚型 GalR1 和 GalR2 来调节大脑中的癫痫发作。为了生成能够区分 GalR1 和 GalR2 的系统有效的甘丙肽受体配体，对 GalR1 偏好性类似物 Gal-B2（或 NAX 5055）进行了合理的重新设计，得到了 GalR2 偏好性类似物。对 N 端主链进行系统截断得到 [N-Me，des-Sar]Gal-B2，其中含有 N-甲基色氨酸。这种类似物对 GalR2 的结合表现出 18 倍的偏好性，保持激动剂活性，并在腹腔给药后在小鼠中表现出有效的抗惊厥活性。
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Developing novel antiepileptic drugs: characterization of NAX 5055, a systemically-active galanin analog, in epilepsy models.开发新型抗癫痫药物：在癫痫模型中对具有全身活性的甘丙肽类似物NAX 5055的特性研究。
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