title: Use of a dipeptide chemical library in the development of non-peptide tachykinin NK3 receptor selective antagonists.
abstract: The use of a dipeptide library as the source of a micromolar chemical lead compound for the human tachykinin NK3 receptor is described. The screening of a dipeptide library through a cloned human NK3 receptor binding assay resulted in the identification of Boc(S)Phe(S)PheNH2 (1), which has subsequently been developed, following a 'peptoid' design strategy, into a series of high-affinity NK3 receptor selective antagonists. The structure-activity relationship of the C-terminal portion of this dipeptide lead was first explored and led to the identification of the urea derivative Boc(S)Phe(R)alphaMePheNH(CH2)7NHCONH2 (41, PD157672). This modified dipeptide has a Ke of 7 nM in blocking senktide-induced increases in intracellular calcium levels in human NK3 receptors stably expressed in CHO cells. Subsequent optimization of the N-terminal BocPhe group and the alphaMePhe residue side chain of 41 led to the identification of [S-(R*,S*)]-[2-(2,3-difluorophenyl)-1-methyl-1-[(7-ureidoheptyl)ca r bamoyl]ethyl]carbamic acid 2-methyl-1-phenylpropyl ester (60, PD161182), a non-peptide NK3 receptor selective antagonist. Compound 60 blocks the senktide-evoked increases in intracellular calcium levels in cloned human NK3 receptors stably expressed in CHO cells with Ke of 0.9 nM.
authors.affiliation: Parke-Davis Neuroscience Research Centre, Cambridge University Forvie Site, U.K.
authors.forename: P
authors.initials: P
authors.lastname: Boden
authors.forename: J M
authors.initials: JM
authors.lastname: Eden
authors.forename: J
authors.initials: J
authors.lastname: Hodgson
authors.forename: D C
authors.initials: DC
authors.lastname: Horwell
authors.forename: J
authors.initials: J
authors.lastname: Hughes
authors.forename: A T
authors.initials: AT
authors.lastname: McKnight
authors.forename: R A
authors.initials: RA
authors.lastname: Lewthwaite
authors.forename: M C
authors.initials: MC
authors.lastname: Pritchard
authors.forename: J
authors.initials: J
authors.lastname: Raphy
authors.forename: K
authors.initials: K
authors.lastname: Meecham
authors.forename: G S
authors.initials: GS
authors.lastname: Ratcliffe
authors.forename: N
authors.initials: N
authors.lastname: Suman-Chauhan
authors.forename: G N
authors.initials: GN
authors.lastname: Woodruff
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004151:Dipeptides / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D034444:Peptoids; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004151:Dipeptides; D034444:Peptoids; D018042:Receptors, Neurokinin-3