Patacchini R, Quartara L, Rovero P, Goso C, Maggi C A
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
J Pharmacol Exp Ther. 1993 Jan;264(1):17-21.
The mammalian tachykinins, neurokinin A (NKA) and NKA(4-10), along with the tachykinin NK2 receptor-selective antagonist MEN 10,376, were compared to their C-terminal free acid derivatives, NKA-OH, NKA(4-10)-OH and MEN 10,456, respectively, on several in vitro bioassays for NK1, NK2 and NK3 tachykinin receptors. NKA-OH and NKA(4-10)-OH were much weaker agonists than NKA or NKA(4-10) in the endothelium-deprived rabbit pulmonary artery (endowed with NK2A receptors) and in the guinea pig isolated bronchus (endowed with NK2A and NK1 receptors), where they produced submaximal contractile responses, and were inactive in the hamster isolated trachea (endowed with NK2B receptors) and in the rat isolated portal vein (endowed with NK3 receptors). At NK1 receptors of the guinea pig isolated ileum, NKA-OH produced weak agonist responses, whereas NKA(4-10)-OH was ineffective. In sharp contrast, MEN 10,456, while maintaining the same antagonist potency of the parent compound MEN 10,376 in the rabbit pulmonary artery and hamster isolated trachea, developed a clear-cut agonist character in the rat isolated portal vein, guinea pig isolated ileum and guinea pig isolated bronchus. The agonist responses produced by MEN 10,456 (10 microM) were reduced by MEN 10,376 in the guinea pig isolated bronchus and by the NK1 receptor antagonist GR 82,334 in the guinea pig isolated ileum. These results, although indicating the importance of C-terminal amidation for the agonist activity of natural tachykinins, suggest that the C-terminal amide group may not be directly involved in stimulation of the tachykinin receptors, but could induce agonist activity through a conformation effect.
将哺乳动物速激肽、神经激肽A（NKA）和NKA(4 - 10)，连同速激肽NK2受体选择性拮抗剂MEN 10,376，分别与其C末端游离酸衍生物NKA - OH、NKA(4 - 10) - OH和MEN 10,456，在针对NK1、NK2和NK3速激肽受体的多种体外生物测定中进行了比较。在去内皮的兔肺动脉（具有NK2A受体）和豚鼠离体支气管（具有NK2A和NK1受体）中，NKA - OH和NKA(4 - 10) - OH作为激动剂的活性比NKA或NKA(4 - 10)弱得多，它们产生的收缩反应未达最大值，且在仓鼠离体气管（具有NK2B受体）和大鼠离体门静脉（具有NK3受体）中无活性。在豚鼠离体回肠的NK1受体上，NKA - OH产生微弱的激动剂反应，而NKA(4 - 10) - OH无作用。形成鲜明对比的是，MEN 10,456在兔肺动脉和仓鼠离体气管中保持了母体化合物MEN 10,376相同的拮抗剂效力，但在大鼠离体门静脉、豚鼠离体回肠和豚鼠离体支气管中表现出明显的激动剂特性。在豚鼠离体支气管中，MEN 10,376可降低MEN 10,456（10 microM）产生的激动剂反应；在豚鼠离体回肠中，NK1受体拮抗剂GR 82,334可降低该反应。这些结果虽然表明C末端酰胺化对于天然速激肽激动剂活性的重要性，但提示C末端酰胺基团可能不直接参与速激肽受体的刺激，而是通过构象效应诱导激动剂活性。
