Effect of nepadutant at tachykinin NK2 receptors in human intestine and urinary bladder

We have characterized the action of the tachykinin NK2 receptor antagonist nepadutant (c{[(beta-D-GlcNAc)Asn-Asp-Trp-Phe-Dpr-Leu]c(2 beta-5 beta)}) in the human isolated ileum, colon and urinary bladder. Nepadutant (30-1000 nM) competitively antagonized neurokinin A- or [beta Ala(8)]neurokinin A-(4-10)-induced contractions in all tissues, with p K-B = 8.3 (ileum and colon) and pK(B) = 8.5 (bladder). In contrast, the nonpeptide tachykinin NK2 receptor antagonist SR 48968 (or (S)-N-methyl-N [4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl) butyl] benzamide) (30-1000 nM) produced insurmountable antagonism in all preparations. The tachykinin NK2 receptor blockade produced by nepadutant in the colon was fully reversed by washout, whereas that produced by SR 48968 was not. Nepadutant (1 mu M) greatly reduced (by 70-80%) the nonadrenergic noncholinergic (NANC) contractile off-response evolved by electrical field stimulation in the human ileum, and almost abolished it in the presence of the tachykinin NK1 receptor antagonist GR 82334 (or: [[(S,S) Pro-Leu (spiro-gamma-lactam)](9,10),Trp(11)]Physalaemin(1-11)) (1 mu M). The present results show that nepadutant is a potent, competitive and reversible antagonist at human tachykinin NK2 receptors and provide further evidence that tachykinins act as excitatory NANC neurotransmitters in the human small intestine. (C) 2000 Elsevier Science B.V. All rights reserved.