A novel tachykinin NK2 receptor antagonist prevents motility-stimulating effects of neurokinin A in small intestine

1 MEN 11420 (nepadutant) is a potent, selective and competitive antagonist of tachykinin NK2 receptors. 2 The objective of the present study was to assess the capability of the dr ug to antagonize the stimulatory effects of neurokinin A (NKA) on gastroint estinal motility, as well as to change the fasting migrating motor complex (MMC). 3 Thirty-four male volunteers were randomized to treatment with either plac ebo or MEN 11420 in a double-blinded manner. Effects of MEN 11420 (8 mg int ravenously) were evaluated as changes in phases I, II and III of MMC as wel l as contraction frequency, amplitude and motility index during baseline co nditions and during stimulation of motility using NKA (125 pmol kg(-1) min( -1) intravenously). 4 NKA preceded by placebo increased the fraction of time occupied by phase II, increased contraction frequency, amplitude and motility index. 5 MEN 11420 effectively antagonized the motility-stimulating effects of NKA . MEN 11420 reduced the phase II-stimulating effect of NKA. In addition, th e stimulatory effect of NKA on contraction frequency and amplitude, as well as motility index were inhibited by MEN 11420. MEN 11420 did not affect th e characteristics of MMC during saline infusion. 6 Plasma levels of MEN 11420 peaked during the first hour after infusion an d decreased to less than half during the first 2 h. 7 In conclusion, intravenous MEN 11420 effectively inhibited NKA-stimulated , but not basal gastrointestinal motility, and was well tolerated by all su bjects.