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.
Chorev
M
M
Department of Pharmaceutical Chemistry, Hebrew University of Jerusalem, Israel.
Roubini
E
E
Gilon
C
C
Selinger
Z
Z
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
D010879:Piperazines; D000077489:Piperazine; D013373:Substance P; D006909:Hydroxyproline