Conformationally constrained substance P analogues:: The total synthesis of a constrained peptidomimetic for the Phe7-Phe8 region

A lactam-based peptidomimetic for the Phe(7)-Phe(8) region of substance P has been synthesized. The synthesis used an anodic amide oxidation to selectively functionalize the C-5-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 Phe(7)-Phes(8) 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 Phe(7) constrained, and the original 3-phenylproline was converted into a substance P analogue having only Phe(8) constrained. All of the analogues were examined for their ability to displace substance P from its NK-1 receptor.