title: Characterization of ibodutant at NK(2) receptor in human colon.
abstract: We have characterized the pharmacological profile of the nonpeptide tachykinin NK2 receptor antagonist ibodutant (MEN15596) through radioligand binding and contractility assays in the human colon smooth muscle. The antagonist affinity of ibodutant was evaluated through concentration-dependent inhibition curves at the [(125)I]NKA specific binding by using membranes prepared from human colon smooth muscle. In this assay the affinity of ibodutant (pKi 9.9) was compared to that of other two selective NK2 receptor antagonists, nepadutant (pKi 8.4) and saredutant (pKi 9.2). The antagonist potency of ibodutant was evaluated towards the [βAla(8)]NKA(4-10)-mediated contractions of human colon smooth muscle strips. In this assay ibodutant (3, 10, 30 and 100 nM) induced a concentration-dependent rightward shift of the [βAla(8)]NKA(4-10) concentration-response curves without depressing the maximal contractile effect. The analysis of the curves yielded a Schild-plot linear regression with a slope not different from unity (1.02), thus indicating a surmountable antagonist behavior. The calculated apparent antagonist potency as pKB value was 9.1. No sex related differences were observed in NK2 receptor pharmacology for [βAla(8)]NKA(4-10) or ibodutant in colonic strips obtained from male or female patients. Reversibility experiments of tachykinin NK2 receptor blockade indicated that the inhibition of the agonist-induced contractions in preparations pre-exposed to ibodutant, and afterwards subjected to repeated washing cycles remained almost constant showing no sign of recovery during the 3h observation period. Overall, the present study indicates ibodutant as a potent tachykinin NK2 receptor antagonist in the human colon tissue, also endowed with a persistent duration of action.
authors: Department of Pharmacology, Menarini Ricerche S.p.A., 50131 Firenze, Italy. psanticioli@menarini-ricerche.it
authors: Paolo
authors: P
authors: Santicioli
authors: Stefania
authors: S
authors: Meini
authors: Sandro
authors: S
authors: Giuliani
authors: Claudio
authors: C
authors: Catalani
authors: Paolo
authors: P
authors: Bechi
authors: Sara
authors: S
authors: Riccadonna
authors: Maria Novella
authors: MN
authors: Ringressi
authors: Carlo Alberto
authors: CA
authors: Maggi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides / Q000494:pharmacology; D001667:Binding, Competitive; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D004151:Dipeptides / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011869:Radioligand Assay; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D004151:Dipeptides; C107754:MEN 11420; D010456:Peptides, Cyclic; D010880:Piperidines; D018041:Receptors, Neurokinin-2; D013876:Thiophenes; C556791:ibodutant; C073839:SR 48968