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

1,4‐Piperazine and 4‐hydroxy proline, 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 arid 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.