MEN-11420 (NEPADUTANT), A NOVEL GLYCOSYLATED BICYCLIC PEPTIDE TACHYKININ NK2 RECEPTOR ANTAGONIST

1 The pharmacological profile was studied of MEN 11420, or cycle{ [Asn (beta-D-GlcNAc)-Asp-Trp-Phe-Dap-Leu]cyclo(2 beta-5 beta)}, a glycosyla ted derivative of the potent, selective, conformationally-constrained tachykinin NK2 receptor antagonist MEN 10627 (cyclo(Met-Asp-Trp-Phe-Da p-leu)cyclo(2 beta-5 beta)). 2 MEN 11420 competitively bound with high affinity to the human NK2 receptor stably transfected in CHO cells, d isplacing radiolabelled [I-125]-neurokinin A and [H-3]-SR 48968 with K -i values of 2.5+/-0.7 nM (n = 6) and 2.6 +/- 0.4 nM (n = 3), respecti vely. 3 MEN 11420 showed negligible binding affinity (pIC(50)<6) at 50 different receptors (including tachykinin NK1 and NK3 receptors) and ion channels. 4 In the rabbit isolated pulmonary artery and rat urinar y bladder MEN 11420 potently and competitively antagonized tachykinin NK2 receptor-mediated contractions (pK(B)= 8.6 +/- 0.07, n = 10, and 9 .0 +/- 0.04, n = 12; Schild plot slope = -1.06 (95% c.l. =-1.3; -0.8) and -1.17 (95% c.l. = -1.3; -1.0), respectively). MEN 11420 produced a n insurmountable antagonism at NK2 receptors in the hamster trachea an d mouse urinary bladder. However, in both preparations, the effect of MEN 11420 was reverted by washout and an apparent pK(B) of 10.2 +/- 0. 14, n= 9, and 9.8 +/- 0.15, n=9, was calculated in the hamster trachea and mouse urinary bladder, respectively. 5 MEN 11420 showed low affin ity (pK(B) < 6) at guinea-pig and rat tachykinin NK1 (guinea-pig ileum and rat urinary bladder) and NK3 (guinea-pig ileum and rat portal vei n) receptors. On the whole, the affinities (potency and selectivity) s howed by MEN 11420 for different tachykinin receptors, measured either in binding or in functional bioassays, were similar to those shown by the parent compound, MEN 10627. 6 The in vivo antagonism of the contr actions produced by [beta Ala(8)]neurokinin A(4-10) (1 nmol kg(-1)) wa s observed after intravenous (dose range: 1-10 nmol kg(-1)), intranasa l (3-10 nmol kg(-1)), intrarectal (30-100 nmol kg(-1)) and intraduoden al (100-300 nmol kg(-1)) administration of MEN 11420. MEN 11420 was mo re potent (about 10 fold) and longer lasting than its parent compound MEN 10627, possibly due to a greater metabolic stability. 7 A dose of MEN 11420 (100 nmol kg(-1), i.v.), that produced potent and long lasti ng inhibition of the contraction of the rat urinary bladder induced by challenge with the NK2 selective receptor agonist [beta Ala(8)]neurok inin A(4-10) (10-300 nmol kg(-1)), was without effect on the responses produced by the NK1 receptor selective agonist [Sar(9)]substance P su lphone (1-10 nmol kg(-1)). 8 These findings indicate that MEN 11420 is a potent and selective tachykinin NK2 receptor antagonist. The introd uction of a sugar moiety did not produce major changes in the affinity profile of this antagonist as compared to MEN 10627, but markedly imp roved its in vivo potency and duration of action. With these character istics, MEN 11420 is a suitable candidate for studying the pathophysio logical significance of tachykinin NK2 receptors in humans.