Toward nonpeptidal substance P mimetic analogues: design, synthesis, and biological activity.

1,4-Piperazine and 4-hydroxyproline, two small cyclic polyfunctional systems with defined stereochemistry, were introduced as "molecular scaffolds." We define a "bioactive topology," which is a derived putative low-energy conformation obtained through theoretical conformational analysis of substance P. Substitution of these molecular scaffolds by pharmacophors characteristic of the bioactive topology of the C-terminal hexapeptide of substance P resulted in active, partially nonpeptidal substance P mimetic agonists. The study discusses the concepts and tools used to achieve this structural transformation, and points out the need to address flexibility-rigidity issues in an attempt to maintain sufficient molecular plasticity.