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.

The synthesis of bicyclic piperazinone and related derivatives.

We have been examining synthetic approaches to conformationally restricted peptide building blocks that would allow for the construction of a variety of possible structures in a straight-forward, general way (1). To date, this effort has focused on developing the chemistry needed to rapidly imbed sections of a peptide backbone into a bicyclic or polycyclic ring skeleton (2-4). Such a transformation is accomplished by replacing spacially close hydrogens in a desired conformation with an appropriately sized carbon bridge. The potential advantages of this approach include the preservation of both the peptide backbone and the side chains in the analog, the ability to control the orientation of the side chains relative to each other, the increased hydrolytic stability of the analog, and the ease with which new analogs can be designed. The potential disadvantages of this approach include the difficulty associated with synthesizing the analogs and the steric size of the bridges added. In this chapter, a convenient preparation of analogs having the general structure of I (Fig. 1) is described. Figure 1.

Conformational probes for elucidating the nature of substance P binding to the NK1 receptor: initial efforts to map the Phe7-Phe8 region.

Three substance P analogs with conformation constraints in the Phe7-Phe8 region have been prepared in connection with an effort to differentiate two families of potential conformations for the binding of substance P to its NK1 receptor. While the analogs did not bind the NK1 receptor with high affinity, the synthesis of the analogs demonstrated the utility of a general method for constructing piperazinone based peptidomimetics.