Asahi Shuichi, Egashira Shin-Ichiro, Matsuda Masao, Iwaasa Hisashi, Kanatani Akio, Ohkubo Mitsuru, Ihara Masaki, Morishima Hajime
Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo-3, Tsukuba 300-2611, Ibaraki, Japan.
Bioorg Med Chem Lett. 2003 Jan 6;13(1):111-3. doi: 10.1016/s0960-894x(02)00851-x.
Investigation of L-alanine and D-amino acid replacement of orexin-B revealed that three L-leucine residues at the positions of 11, 14, and 15 in orexin-B were important to show selectivity for the orexin-2 receptor (OX(2)) over the orexin-1 receptor (OX(1)). L-Alanine substitution at position 11 and D-leucine substitution at positions 14 and 15 maintained the potency of orexin-B to mobilize Ca(2+) in CHO cells expressing the OX(2), while their potency for the OX(1) was significantly reduced. In combined substitutions, we identified that [Ala(11), D-Leu(15)]orexin-B showed a 400-fold selectivity for the OX(2) (EC(50)=0.13nM) over OX(1) (EC(50)=52nM). [Ala(11), D-Leu(15)]orexin-B is a beneficial tool for addressing the functional roles of the OX(2).
对食欲素 - B中L - 丙氨酸和D - 氨基酸替代物的研究表明，食欲素 - B中第11、14和15位的三个L - 亮氨酸残基对于显示对食欲素 - 2受体（OX(2)）相对于食欲素 - 1受体（OX(1)）的选择性很重要。第11位的L - 丙氨酸替代和第14、15位的D - 亮氨酸替代保持了食欲素 - B在表达OX(2)的CHO细胞中动员Ca(2+)的效力，而它们对OX(1)的效力则显著降低。在联合替代中，我们发现[Ala(11), D - Leu(15)]食欲素 - B对OX(2)（EC(50)=0.13nM）相对于OX(1)（EC(50)=52nM）表现出400倍的选择性。[Ala(11), D - Leu(15)]食欲素 - B是研究OX(2)功能作用的有益工具。
