Structure—Activity Relationships of Rat Neuromedin U For Smooth Muscle Contraction

Abstract

Rat neuromedin U (r-NMU) and its fragment peptide amides were synthesized by solid-phase methodology. Using a chicken crop smooth muscle contraction assay, the potency of r-NMU and its fragments relative to porcine neuromedin U-8 (p-NMU-8) was r-NMU: 10.25 ±2.88, r-NMU (6—23): 8.01 ±1.04, r-NMU (10—23): 2.76 ±0.46, r-NMU (13—23): 2.81 ±0.52, and r-NMU (16—23): 0.88 ±0.19, respectively. Two heptapeptides, r-NMU (17—23) and r-NMU (16—22), had a relative potency of 0.61 and 0.03 respectively, and elicited maximal contraction at a dose of 10 pm to a similar degree to p-NMU-8. The other shorter C-terminal fragments did not elicit the maximal contraction or any activity. In a rat uterus contraction assay, r-NMU (13—23), but not r-NMU (16—23), at a dose of 4 nM retained as high a stimulatory activity as r-NMU itself. r-NMU (17—22) was the smallest peptide fragment to elicit the maximal sustained contraction at 10 /jm. These results indicate that the amino acid sequence Phe-Leu-Phe-Arg-Pro-Arg, corresponding to positions 17 to 22 of r-NMU, may be essential for contractile activity. N-terminal peptide segments Tyr-Gln-Gly-Pro corresponding to positions 6 to 9, and Ser-Gly-Gly corresponding to positions 13 to 15, appear to be of special importance for potent activity. © 1991, The Pharmaceutical Society of Japan. All rights reserved.