Neuropeptide Y (NPY) Y4 receptor selective agonists based on NPY(32-36):: Development of an anorectic Y4 receptor selective agonist with picomolar affinity
Neuropeptide Y (NPY) Y4 receptor selective agonists based on NPY(32-36):: Development of an anorectic Y4 receptor selective agonist with picomolar affinity
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DOI：
10.1021/jm050907d
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发表时间：
2006-04-20
影响因子：
7.3
通讯作者：
Parker, EM
中科院分区：
文献类型：
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作者：
Balasubramaniam, A;Mullins, DE;Parker, EM
我们之前已经证明[Cys-Trp-Arg-Nva-Arg-Tyr-NH2](2)， 1是一种中等选择性神经肽Y (NPY) Y-4受体激动剂。为了提高Y-4受体的选择性和效力，我们研究了使用含有二、三或四三乙基炔间隔剂的不同二氨基二羧酸对H-Trp-Arg-Nva-Arg-Tyr-NH2二聚化的影响。这些平行二聚体2A、2B、3、4A和4B，以及相应的线性串联二聚体和三聚体类似物5和6，与1相比，对Y-4受体具有更高的选择性和亲和力（表1）。在2,7- d / l -二氨基亚酰基酸衍生的二聚体7中，Trp和Nva分别被Tyr和Leu取代，产生了具有小摩尔亲和力的优越的Y-4选择性激动剂。腹腔注射7能有效抑制禁食小鼠的食物摄入。此外，在野生型小鼠中，7 （ip）抑制了食物摄入，而在Y-4（-/-）敲除小鼠中则没有，这证实了7对食物摄入的作用不是由于全局效应，而是特异性介导Y-4受体。
We have previously shown [Cys-Trp-Arg-Nva-Arg-Tyr-NH2](2), 1, to be a moderately selective neuropeptide Y (NPY) Y-4 receptor agonist. Toward improving the selectivity and potency for Y-4 receptors, we studied the effects of dimerizing H-Trp-Arg-Nva-Arg-Tyr-NH2 using various diamino-dicarboxylic acids containing either di, tri-, or tetra triethyl e ne spacers. These parallel dimers, 2A, 2B, 3, 4A, and 4B, and the corresponding linear tandem dimer and trimer analogues, 5 and 6, had enhanced selectivity and affinity for Y-4 receptors compared to 1 (Table 1). Substitution of Trp and Nva with Tyr and Leu, respectively, as in 2,7-D/L-diaminosuberic acid derivatized dimer, 7, resulted in a superior Y-4 selective agonist with picomolar affinity. Intraperitoneal (ip) injection of 7 potently inhibited food intake in fasted mice. Moreover, 7 (ip) inhibited the food intake in wild-type mice and not in Y-4(-/-) knock-out mice, confirming that the actions of 7 on food intake are not due to global effects, but specifically mediated Y-4 receptors.