Structure-Activity Relationships of Neuromedin U.IV. Absolute Requirement of the Arginine Residue at Position 7 of Dog Neuromedin U-8 for Contractile Activity

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To examine the role of both Arg residues at positions 5 and 7 of dog neuromedin U-8 (d-NMU-8; pGlu^1-Phe-Leu-Phe-Arg^5-Pro-Arg^7-Asn^8-NH_2) for smooth muscle contractile activity on isolated chicken crop, d-NMU-8 analogs were synthesized where either Arg residue was systematically replaced by various amino acids [X : Ala, Thr, Glu, Gln, Lys, Orn, His, citrulline (Cit) or homoarginine (Har)]. All [X^5]-d-NMU-8,except for [Glu^5]- and [Des-Arg^5]-d-NMU-8,were full agnists, although their affinities to NMU receptors were decreased.No [X^7]-d-NMU-8 showed contractile activity even at concentrations of 10^<-5> mol/l, except for [Har^7]-d-NMU-8,which retained weak biological activity. These analogs had no antagonistic activity against porcine neuromedin U-8 (p-NMU-8). The results revealed that Arg^7 of d-NMU-8 is indispensable for receptor binding and activation to induce smooth muscle contraction, and the guanidino group of the side chain at position 7,but not at position 5,is strictly recognized by NMU receptors in the chicken crop.
公益社団法人日本薬学会の論文
2000-08-01