title: Toward nonpeptidal substance P mimetic analogues: design, synthesis, and biological activity.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, Hebrew University of Jerusalem, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Chorev
authors.forename: E
authors.initials: E
authors.lastname: Roubini
authors.forename: C
authors.initials: C
authors.lastname: Gilon
authors.forename: Z
authors.initials: Z
authors.lastname: Selinger
mesh_terms: D000595:Amino Acid Sequence; D015195:Drug Design; D006909:Hydroxyproline / Q000737:chemistry; D008969:Molecular Sequence Data; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines; D011487:Protein Conformation; D012689:Sequence Homology, Nucleic Acid; D013373:Substance P / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism
chemical_list: D010879:Piperazines; D000077489:Piperazine; D013373:Substance P; D006909:Hydroxyproline