MEN 11420 (Nepadutant), a novel glycosylated bicyclic peptide tachykinin NK 2 receptor antagonist

The pharmacological profile was studied of MEN 11420, or cyclo{[Asn(β‐D‐GlcNAc)‐Asp‐Trp‐Phe‐Dap‐Leu]cyclo(2β‐5β)}, a glycosylated derivative of the potent, selective, conformationally‐constrained tachykinin NK 2 receptor antagonist MEN 10627 (cyclo(Met‐Asp‐Trp‐Phe‐Dap‐Leu)cyclo(2β‐5β)). MEN 11420 competitively bound with high affinity to the human NK 2 receptor stably transfected in CHO cells, displacing radiolabelled [ 125 I]‐neurokinin A and [ 3 H]‐SR 48968 with K i values of 2.5±0.7 n M ( n =6) and 2.6±0.4 n M ( n =3), respectively. MEN 11420 showed negligible binding affinity (pIC 50 <6) at 50 different receptors (including tachykinin NK 1 and NK 3 receptors) and ion channels. In the rabbit isolated pulmonary artery and rat urinary bladder MEN 11420 potently and competitively antagonized tachykinin NK 2 receptor‐mediated contractions (p K 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 an insurmountable antagonism at NK 2 receptors in the hamster trachea and mouse urinary bladder. However, in both preparations, the effect of MEN 11420 was reverted by washout and an apparent p K 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. MEN 11420 showed low affinity (p K B <6) at guinea‐pig and rat tachykinin NK 1 (guinea‐pig ileum and rat urinary bladder) and NK 3 (guinea‐pig ileum and rat portal vein) receptors. On the whole, the affinities (potency and selectivity) showed 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. The in vivo antagonism of the contractions produced by [βAla 8 ]neurokinin A(4–10) (1 nmol kg −1 ) was observed after intravenous (dose range: 1–10 nmol kg −1 ), intranasal (3–10 nmol kg −1 ), intrarectal (30–100 nmol kg −1 ) and intraduodenal (100–300 nmol kg −1 ) administration of MEN 11420. MEN 11420 was more potent (about 10 fold) and longer lasting than its parent compound MEN 10627, possibly due to a greater metabolic stability. A dose of MEN 11420 (100 nmol kg −1 , i.v.), that produced potent and long lasting inhibition of the contraction of the rat urinary bladder induced by challenge with the NK 2 selective receptor agonist [βAla 8 ]neurokinin A(4–10) (10–300 nmol kg −1 ), was without effect on the responses produced by the NK 1 receptor selective agonist [Sar 9 ]substance P sulphone (1–10 nmol kg −1 ). These findings indicate that MEN 11420 is a potent and selective tachykinin NK 2 receptor antagonist. The introduction of a sugar moiety did not produce major changes in the affinity profile of this antagonist as compared to MEN 10627, but markedly improved its in vivo potency and duration of action. With these characteristics, MEN 11420 is a suitable candidate for studying the pathophysiological significance of tachykinin NK 2 receptors in humans.British Journal of Pharmacology (1998) 123 , 81–91; doi: 10.1038/sj.bjp.0701587