Structure-Antagonistic Activity Relationships of an NK-2 Tachykinin Receptor Antagonist, L-659,877 and Its Analogues

  • Ha, Jong-Myung (Department of Chemistry, College of Natural Sciences, Pusan Women's University) ;
  • Shin, Song-Yub (Peptide Engineering Research Unit, Korea Research Institute of Bioscience and Biotechnology, KIST) ;
  • Hong, Hea-Nam (Department of Anatomy, College of Medicine, University of Ulsan) ;
  • Suh, Duk-Joon (Department of Physiology, College of Medicine, Dong-A University) ;
  • Jang, Tae-Sik (Department of Chemistry, College of Natural Sciences, Pusan National University) ;
  • Kang, Shin-Won (Department of Chemistry, College of Natural Sciences, Pusan National University) ;
  • Kuean, Sun-Jin (Department of Food Science & Nutrition, College of Home Economics, Pusan National University) ;
  • Ha, Bae-Jin (Department of Chemistry, College of Natural Sciences, Pusan Women's University)
  • Received : 1996.05.02
  • Published : 1996.09.30


To investigate the structure-antagonistic relationship of the cyclohexapeptide L-659,877, a selective NK-2 tachykinin receptor antagonist, seven analogues were chemically synthesized by a solid phase method. The agonistic and antagonistic activities of the analogues were evaluated by contraction assay using the smooth muscle of guinea pig trachea (GPT) containing the NK-2 receptor. It was shown that the aromatic ring of Phe at position 3 and the sulfur group of Met at position 6 in L-659,877 were essential for binding to the NK-2 receptor. Decrease in antagonistic activity of L-659,877 caused by substituting Leu for Nle at position 5 indicates that the ${\gamma}$ methyl group and side chain length of Leu plays an important role in its antagonistic action. Although the activity was slightly lower than L-659,877, cyclo $[{\beta}Ala^{8}]NKA(4-10)$ (analogue 1) showed potential antagonistic activity for the NK-2 receptor. It was confirmed that the expansion of the ring in L-659,877 by substitution of ${\beta}Ala$ for Gly at position 4 stabilized its conformation monitored by CD spectra. The results suggest that analogue 1 can be used as a new leader compound to design a more powerful, selective, and stable NK-2 receptor antagonist.


antagonist;cyclic hexapeptide;guinea pig trachea;L-659,877;neurokinin-2 (NK-2)


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