title: MEN 10,627, a novel polycyclic peptide antagonist of tachykinin NK2 receptors.
abstract: 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 first example of a polycyclic peptide tachykinin NK2 receptor antagonist. MEN 10,627 is endowed with high affinity for NK2 receptor expressed in various species with pKB values ranging between 10.1 (hamster trachea) and 8.1 (rabbit pulmonary artery). The antagonism is of competitive type in both functional and radioligand binding assays. A 100- to 10,000-fold selectivity was found vs. NK1 or NK3 receptors expressed in various species. As an NK2 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 antagonist SR 48,968 [(S)-N-methyl-N[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl) butyl]benzamide], whereas the converse is true for the rabbit NK2 receptor. Furthermore, MEN 10,627 is, up to micromolar concentrations, devoid of antagonist properties toward a wide range of transmitters of both peptide and nonpeptide nature. In urethane-anesthetized rats in vivo, MEN 10,627 (10-100 nmol/kg i.v.) produced long-lasting inhibition of contraction of the urinary bladder and duodenum produced by i.v. administration of the NK2 receptor agonist [beta Ala8]NKA(4-10), without affecting the responses produced by i.v. administration of the NK1 receptor agonist [Sar9]SP sulfone or acetylcholine. In anesthetized rats, both MEN 10,627 and SR 48,968 blocked urinary bladder contraction induced by the NK2 receptor agonist after intravenous, intranasal or intraduodenal administration. Equieffective doses of MEN 10,627 producing about 50% inhibition of the response to [beta Ala8]NKA(4-10) in the rat urinary bladder in vivo, were 0.01, 0.03 and 3 mumol/kg after intravenous, intranasal and intraduodenal administration, respectively. The corresponding doses of SR 48,968 were 0.03, 0.1 and 1 mumol/kg, after intravenous, intranasal and intraduodenal administration, respectively. In conclusion, MEN 10,627 is a potent and selective NK2 receptor antagonist, endowed with high potency and long duration of action in vivo, which is not restricted to parenteral administration.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
authors.forename: C A
authors.initials: CA
authors.lastname: Maggi
authors.forename: M
authors.initials: M
authors.lastname: Astolfi
authors.forename: S
authors.initials: S
authors.lastname: Giuliani
authors.forename: C
authors.initials: C
authors.lastname: Goso
authors.forename: S
authors.initials: S
authors.lastname: Manzini
authors.forename: S
authors.initials: S
authors.lastname: Meini
authors.forename: R
authors.initials: R
authors.lastname: Patacchini
authors.forename: V
authors.initials: V
authors.lastname: Pavone
authors.forename: C
authors.initials: C
authors.lastname: Pedone
authors.forename: L
authors.initials: L
authors.lastname: Quartara
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology
chemical_list: D001549:Benzamides; D010456:Peptides, Cyclic; D010880:Piperidines; D018041:Receptors, Neurokinin-2; C073361:cyclo(Gln-Trp-Phe-Gly-Leu-Met); C090951:MEN 10627; C073839:SR 48968