MEN-10,627, A NOVEL POLYCYCLIC PEPTIDE ANTAGONIST OF TACHYKININ NK2 RECEPTORS

We describe the in vitro and in vivo pharmacological properties of MEN 10,627 or cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2 beta-5 beta), the fir st example of a polycyclic peptide tachykinin NK, receptor antagonist. MEN 10,627 is endowed with high affinity for NK2 receptor expressed i n various species with pK(B) values ranging between 10.1 (hamster trac hea) and 8.1 (rabbit pulmonary artery). The antagonism is of competiti ve type in both functional and radioligand binding assays. A 100- to 1 0,000-fold selectivity was found vs. NK1 or NK3 receptors expressed in various species. As an NK, receptor antagonist, MEN 10,627 is 10- to 100-fold more potent than the monocyclic peptide antagonist L 659,877 or cyclo(Met-Gln-Trp-Phe-Gly-Leu). At the hamster NK2 receptor, MEN 10 ,627 is about 30-fold more potent than the nonpeptide NK2 receptor ant agonist SR 48,968 peridino)-2-(3,4-di-chlorophenyl)butyl]benzamide], w hereas the converse is true for the rabbit NK2 receptor. Furthermore, MEN 10,627 is, up to micromolar concentrations, devoid of antagonist p roperties toward a wide range of transmitters of both peptide and nonp eptide nature. In urethane-anesthetized rats in vivo, MEN 10,627 (10-1 00 nmol/kg i.v.) produced long-lasting inhibition of contraction of th e urinary bladder acid duodenum produced by i.v. administration of the NK2 receptor agonist [beta Ala(8)]NKA(4-10), without affecting the re sponses produced by i.v. administration of the NK1 receptor agonist [S ar(9)]SP sulfone or acetylcholine. In anesthetized rats, both MEN 10,6 27 and SR 48,968 blocked urinary bladder contraction induced by the NK , receptor agonist after intravenous, intranasal or intraduodenal admi nistration. Equieffective doses of MEN 10,627 producing about 50% inhi bition of the response to [beta Ala(8)]NKA(4-10) in the rat urinary bl adder in vivo, were 0.01, 0.03 and 3 mu mol/kg after intravenous, intr anasal and intraduodenal administration, respectively. The correspondi ng doses of SR 48,968 were 0.03, 0.1 and 1 mu mol/kg, after intravenou s, intranasal and intraduodenal administration, respectively. In concl usion, MEN 10,627 is a potent and selective NK2 receptor antagonist, e ndowed with high potency and long duration of action in vivo, which is not restricted to parenteral administration. Therefore, MEN 10,627 ov ercomes some of the most common drawbacks for the use of peptides as d rugs, and appears as a serious candidate for testing the potential use fulness of NK2 receptor antagonists in humans.