title: Effect of nepadutant at tachykinin NK(2) receptors in human intestine and urinary bladder.
abstract: We have characterized the action of the tachykinin NK(2) 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 pK(B)=8.3 (ileum and colon) and pK(B)=8.5 (bladder). In contrast, the nonpeptide tachykinin NK(2) 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 NK(2) receptor blockade produced by nepadutant in the colon was fully reversed by washout, whereas that produced by SR 48968 was not. Nepadutant (1 microM) greatly reduced (by 70-80%) the nonadrenergic noncholinergic (NANC) contractile off-response evoked by electrical field stimulation in the human ileum, and almost abolished it in the presence of the tachykinin NK(1) receptor antagonist GR 82334 (or: [[(S,S) Pro-Leu (spiro-gamma-lactam)](9,10),Trp(11)]Physalaemin (1-11)) (1 microM). The present results show that nepadutant is a potent, competitive and reversible antagonist at human tachykinin NK(2) receptors and provide further evidence that tachykinins act as excitatory NANC neurotransmitters in the human small intestine.
authors.affiliation: Pharmacology Department, Research Laboratories, Menarini Ricerche SpA, via Rismondo 12/A, 50131, Florence, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Patacchini
authors.forename: S
authors.initials: S
authors.lastname: Giuliani
authors.forename: A
authors.initials: A
authors.lastname: Turini
authors.forename: G
authors.initials: G
authors.lastname: Navarra
authors.forename: C A
authors.initials: CA
authors.lastname: Maggi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D008297:Male; D008875:Middle Aged; D015288:Neurokinin A / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology
chemical_list: D001549:Benzamides; C107754:MEN 11420; D010456:Peptides, Cyclic; D010880:Piperidines; D018041:Receptors, Neurokinin-2; C073839:SR 48968; D015288:Neurokinin A