1 The pharmacological pro®le was studied of MEN 11420, or cyclo{[Asn(b-D-GlcNAc)-Asp-Trp-PheDap-Leu]cyclo(2b-5b)}, a glycosylated derivative of the potent, selective, conformationally-constrained tachykinin NK 2 receptor antagonist MEN 10627 (cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2b-5b)). and ion channels. 4 In the rabbit isolated pulmonary artery and rat urinary bladder MEN 11420 potently and competitively antagonized tachykinin NK 2 receptor-mediated contractions (pK B =8.6+0.07, n=10, and 9.0+0.04, n=12; Schild plot slope=71.06 (95% c.l.=71.3; 70.8) and 71.17 (95% c.l.=71.3; 71.0), respectively). MEN 11420 produced an insurmountable antagonism at NK 2 receptors in the hamster trachea and mouse urinary bladder. However, in both preparations, the eect 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 anity (pK B 56) 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 anities (potency and selectivity) showed by MEN 11420 for dierent tachykinin receptors, measured either in binding or in functional bioassays, were similar to those shown by the parent compound, MEN 10627. ) and intraduodenal (100 ± 300 nmol kg 71 ) 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. 7 A dose of MEN 11420 (100 nmol kg 71 , 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 [bAla 8 ]neurokinin A(4 ± 10) (10 ± 300 nmol kg 71 ), was without eect on the responses produced by the NK 1 receptor selective agonist [Sar 9 ]substance P sulphone (1 ± 10 nmol kg 71 ). 8 These ®ndings 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 anity pro®le 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 signi®cance of tachykinin NK 2 receptors in humans.

1 The e ects of the novel mammalian tachykinin, hemokinin 1 (HEK-1), have been investigated by radioligand binding and functional in vitro and in vivo experiments. 2 Similar to SP (K i =0.13 nM), HEK-1 inhibited in a concentration-dependent manner and with high a nity [ 3 H]-substance P (SP) binding to human NK 1 receptor (K i =0.175 nM) while its a nity for [ 125 I]-neurokinin A (NKA) binding at human NK 2 receptor was markedly lower (K i =560 nM). 3 In isolated bioassays HEK-1 was a full agonist at tachykinin NK 1 , NK 2 and NK 3 receptors. In the rat urinary bladder (RUB) HEK-1 was about 3 fold less potent than SP. In the rabbit pulmonary artery (RPA) HEK-1 and in the guinea-pig ileum (GPI), HEK-1 was about 500 fold less potent than NKA and NKB, respectively. 4 The responses to HEK-1 were antagonized by GR 82334 in RUB (pK B =5.6+0.07), by nepadutant in RPA (pK B =8.6+0.04) and by SR 142801 in GPI (pK B =9.0+0.2) with apparent a nities comparable to that measured against tachykinin NK 1 , NK 2 and NK 3 receptor-selective agonists, respectively. 5 Intravenous HEK-1 produced dose-related decrease of blood pressure in anaesthetized guineapigs (ED 50 =0.1 nmol kg 71 ) and salivary secretion in anaesthetized rats (ED 50 =6 nmol kg 71 ) with potencies similar to that of SP. All these e ects were blocked by the selective tachykinin NK 1 receptor antagonist, SR 140333. 6 We conclude that HEK-1 is a full agonist at tachykinin NK 1 , NK 2 and NK 3 receptors, possesses a remarkable selectivity for NK 1 as compared to NK 2 or NK 3 receptors and acts in vivo experiments with potency similar to that of SP.

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