Regoli D, Escher E, Mizrahi J
Pharmacology. 1984;28(6):301-20. doi: 10.1159/000137979.
Various attempts to developing antagonists for substance P (SP) and related peptides, based on our past experience with angiotensin, kinins, and neurotensin, were unsuccessful. The particular features of SP, namely the high activity of C-terminal partial sequences in some pharmacological tests were used to develop one hexa and several octapeptide antagonists. Weak antagonists were obtained with a single modification, namely the replacement of Leu10 with trp in the sequences SP (6-11), SP (4-11) and SP (1-11). The affinity of octa and undecapeptide antagonists could be increased by using two (in positions 7 and 9 or 7 and 10) or 3 (in position 7, 9 and 10) substitutions of the natural residues with trp. Affinity of antagonists was further increased by replacing Met11 with either Nle or Phe. These new compounds showed some selectivity, [pro4, trp7 ,9, Nle11 ]-SP (4-11) being more potent in the rabbit mesenteric vein than all other octapeptides described in the present study; on the other hand, [pro4, trp7 ,9,10,Phe11]-SP (4-11) was found to be the most potent antagonist of SP and related peptides in the guinea pig ileum and the guinea pig trachea. Both compounds were similarly active in the dog carotid artery. Undecapeptide antagonists, bearing the same structural modifications as the octapeptides, were found to be stimulant in the guinea pig trachea and relaxant in the dog carotid artery. The agonistic property was eliminated by repeated applications of the compounds in guinea pig tracheae, and therefore the compounds could be tested as antagonists. The undecapeptides were found to be much more active antagonists against kasinin and eledoisin than against SP and physalaemin. The data obtained with the octa and undecapeptide antagonists of SP have been used for identification and characterization of SP receptors in various smooth muscles. It appears that SP and related peptides may exert their numerous pharmacological effects by activating more than one receptor type.
基于我们过去在血管紧张素、激肽和神经降压素方面的经验，人们曾多次尝试开发P物质（SP）及相关肽的拮抗剂，但均未成功。利用SP的特殊特性，即在某些药理试验中C末端部分序列具有高活性，开发出了一种六肽和几种八肽拮抗剂。通过单一修饰，即在序列SP(6 - 11)、SP(4 - 11)和SP(1 - 11)中用色氨酸取代亮氨酸10，得到了弱拮抗剂。通过用色氨酸对天然残基进行两个（在第7和9位或第7和10位）或三个（在第7、9和10位）取代，可以提高八肽和十一肽拮抗剂的亲和力。用Nle或Phe取代Met11可进一步提高拮抗剂的亲和力。这些新化合物表现出一定的选择性，[脯氨酸4，色氨酸7,9，Nle11]-SP(4 - 11)在兔肠系膜静脉中的活性比本研究中描述的所有其他八肽都更强；另一方面，[脯氨酸4，色氨酸7,9,10，苯丙氨酸11]-SP(4 - 11)被发现是豚鼠回肠和豚鼠气管中SP及相关肽的最有效拮抗剂。这两种化合物在犬颈动脉中活性相似。与八肽具有相同结构修饰的十一肽拮抗剂在豚鼠气管中具有刺激作用，而在犬颈动脉中具有舒张作用。通过在豚鼠气管中反复应用这些化合物，消除了其激动特性，因此可以将这些化合物作为拮抗剂进行测试。发现十一肽对激肽释放酶和蛙皮素的拮抗活性比对SP和雨蛙肽的拮抗活性强得多。用SP的八肽和十一肽拮抗剂获得的数据已用于鉴定和表征各种平滑肌中的SP受体。似乎SP及相关肽可能通过激活不止一种受体类型来发挥其众多药理作用。
