Use of a dipeptide chemical library in the development of non-peptide tachykinin NK3 receptor selective antagonists.
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.
Boden
P
P
Parke-Davis Neuroscience Research Centre, Cambridge University Forvie Site, U.K.
Eden
J M
JM
Hodgson
J
J
Horwell
D C
DC
Hughes
J
J
McKnight
A T
AT
Lewthwaite
R A
RA
Pritchard
M C
MC
Raphy
J
J
Meecham
K
K
Ratcliffe
G S
GS
Suman-Chauhan
N
N
Woodruff
G N
GN
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
D004151:Dipeptides; D034444:Peptoids; D018042:Receptors, Neurokinin-3