Conformationally constrained substance P analogues: the total synthesis of a constrained peptidomimetic for the Phe7-Phe8 region.
A lactam-based peptidomimetic for the Phe7-Phe8 region of substance P has been synthesized. The synthesis used an anodic amide oxidation to selectively functionalize the C5-position of a 3-phenylproline derivative. The resulting proline derivative was coupled to a Cbz-protected phenylalanine, and an intramolecular reductive amination strategy used to convert the coupled material into a bicyclic piperazinone ring skeleton. The net result was a dipeptide building block that imbedded one of two proposed receptor bound conformations for the Phe7-Phe8 region of substance P into a bicyclic ring skeleton. The building block was then converted into a constrained substance P analogue with the use of solid-phase peptide synthesis. A similar intramolecular reductive amination strategy was used to synthesize a substance P analogue having only Phe7 constrained, and the original 3-phenylproline was converted into a substance P analogue having only Phe8 constrained. All of the analogues were examined for their ability to displace substance P from its NK-1 receptor.
Tong
Y
Y
Department of Chemistry, Washington University, St. Louis, Missouri 63130, USA.
Fobian
Y M
YM
Wu
M
M
Boyd
N D
ND
Moeller
K D
KD
D001667:Binding, Competitive / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D008968:Molecular Conformation; D010649:Phenylalanine / Q000737:chemistry*; D018040:Receptors, Neurokinin-1 / Q000187:drug effects; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013056:Spectrophotometry, Ultraviolet; D013373:Substance P / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology
D018040:Receptors, Neurokinin-1; D013373:Substance P; D010649:Phenylalanine