Balasubramaniam Ambikaipakan, Mullins Deborra E, Lin Shu, Zhai Wexiu, Tao Zhiyong, Dhawan Vikas C, Guzzi Mario, Knittel James J, Slack Katy, Herzog Herbert, Parker Eric M
Division of Gastrointestinal Hormones, Department of Surgery and Interdisciplinary Neurosciences Program, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
J Med Chem. 2006 Apr 20;49(8):2661-5. doi: 10.1021/jm050907d.
We have previously shown Cys-Trp-Arg-Nva-Arg-Tyr-NH(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-NH(2) using various diamino-dicarboxylic acids containing either di-, tri-, or tetramethylene 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.
我们之前已经证明，半胱氨酸-色氨酸-精氨酸-正缬氨酸-精氨酸-酪氨酸-NH(2)（1）是一种中等选择性的神经肽Y（NPY）Y(4)受体激动剂。为了提高对Y(4)受体的选择性和效力，我们研究了使用含有二、三或四亚甲基间隔基的各种二氨基二羧酸使H-色氨酸-精氨酸-正缬氨酸-精氨酸-酪氨酸-NH(2)二聚化的效果。与1相比，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，对Y(4)受体具有更高的选择性和亲和力（表1）。如在2,7-d/l-二氨基辛二酸衍生的二聚体7中，分别用酪氨酸和亮氨酸取代色氨酸和正缬氨酸，得到了一种具有皮摩尔亲和力的优异的Y(4)选择性激动剂。腹腔注射7可有效抑制禁食小鼠的食物摄入量。此外，7（腹腔注射）抑制野生型小鼠的食物摄入，但对Y(4)(-/-)基因敲除小鼠无效，这证实了7对食物摄入的作用不是由于整体效应，而是特异性地通过Y(4)受体介导的。
