Agonistic and Antagonistic Activities of Neuromedin U-8 Analogs Substituted with Glycine or D-Amino Acid on Contractile Activity of Chicken Crop Smooth Muscle Preparations

概要

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To study the structure-actibity relationships of neuromedin U-8 (NMU-8) (H-Tyr-Phe-Leu-Phe-Arg-Pro-Arg-Asn-NH_2) and to develop a NMU-8 antagonist, twenty-three NMU-8 analogs substituted with Gly or the corresponding D-amino acid(s) at positions 1-8 were synthesized by solid-phase techniques. On isolated chicken crop preparations, the contractile activity of the synthetic NMU-8 analogs was compared with that of NMU-8 and their antagonistic activity was assayed against NMU-8. The replacement of Phe^2,Phe^4,Arg^5,Pro^6,Arg^7 or Asn^8 with Gly brought about a drastic decrease of the agonistic activities. Substitution of the corresponding D-amino acid residue for Phe^2,Phe^4,Arg^5,Pro^6 or Asn^8 caused a marked decrease of the agonistic activites, while the replacement of Tyr^1 with D-form enhanced the activity. It was further revealed that [D-Pro^6]-HMU-8 and [D-Leu^3,D-Pro^6]-MNU-8 exerted a non-competitive antagonistic activity against NMU-8 with x values of 5.22±0.12 and 5.34±0.09,respectively. [D-Phe^2,D-Pro^6]-NMU-8,[D-Arg^5,D-Pro^6]-NMU-8 and [D-Pro^6,D-Asn^8]-NMU-8 showed a very weak antagonism. The results indicated that 1) the side chain of each amino acid at positions 2,4,5,6,7 and 8 of NMU-8 is of relative importance for the expression of the contractile activity, and 2) [D-Pro^6]-NMU-8 and its four analogs acted as an antagonist against NMU-8.
社団法人日本薬学会の論文
1991-09-25