Mazarguil H, Gouardères C, Tafani J A, Marcus D, Kotani M, Mollereau C, Roumy M, Zajac J M
Institut de Pharmacologie et de Biologie Structurale, CNRS UMR 5089, 205 Route de Narbonne, 31077, Toulouse Cedex, France.
Peptides. 2001 Sep;22(9):1471-8. doi: 10.1016/s0196-9781(01)00468-5.
A structure-activity study was carried out to determine the importance of the C-terminal amino acids of the octapeptide Neuropeptide FF (NPFF) in binding and agonistic activity. Affinities of NPFF analogues were tested toward NPFF receptors of the rat spinal cord and the human NPFF2 receptors transfected in CHO cells. The activities of these analogues were evaluated by their ability to both inhibit adenylate cyclase in NPFF2 receptor transfected CHO cells and to reverse the effect of nociceptin on acutely dissociated rat dorsal raphe neurons. The substitutions of Phenylalanine8 by a tyrosine, phenylglycine or homophenylalanine were deleterious for high affinity. Similarly, the replacement of Arginine7 by a lysine or D. Arginine induces a loss in affinity. The pharmacological characterization showed that the presence of the amidated Phe8 and Arg7 residues are also extremely critical for activation of anti-opioid effects on dorsal raphe neurons. The sequence of the C-terminal dipeptide seems also to be responsible for the high affinity and the activity on human NPFF2 receptors. The results support the view that a code messaging the molecular interaction toward NPFF-receptors is expressed in the C-terminal region of these peptides but the N-terminal segment is important to gain very high affinity.
开展了一项构效关系研究，以确定八肽神经肽FF（NPFF）的C端氨基酸在结合和激动活性中的重要性。测试了NPFF类似物对大鼠脊髓NPFF受体和转染于CHO细胞中的人NPFF2受体的亲和力。通过这些类似物抑制NPFF2受体转染的CHO细胞中腺苷酸环化酶的能力以及逆转孤啡肽对急性解离的大鼠中缝背核神经元的作用的能力，来评估它们的活性。用酪氨酸、苯甘氨酸或高苯丙氨酸取代苯丙氨酸8对高亲和力有害。同样，用赖氨酸或D-精氨酸取代精氨酸7会导致亲和力丧失。药理学特征表明，酰胺化的苯丙氨酸8和精氨酸7残基的存在对于激活对中缝背核神经元的抗阿片样物质作用也极其关键。C端二肽的序列似乎也决定了对人NPFF2受体的高亲和力和活性。结果支持这样一种观点，即这些肽的C端区域表达了一种编码分子与NPFF受体相互作用的信息，但N端片段对于获得非常高的亲和力很重要。
