Synthesis and biological activity of novel backbone-bicyclic substance-P analogs containing lactam and disulfide bridges.
A biased library of 60 novel backbone-bicyclic Substance P analogs was prepared by the simultaneous multiple peptide synthesis method. The peptides, containing both a lactam and a disulfide ring, were synthesized by combined Boc and Fmoc chemistries, and were cyclized on the resin. Cleavage of the S-benzyl group and oxidation of the sulfhydryl groups was enabled by adaptation of the diphenylsulfoxidetrichloromethylsilane method to solid-phase synthesis. The peptides were screened for NK-1 and NK-3 activity, and were found to be weak agonists.
Bitan
G
G
Department of Organic Chemistry, Hebrew University of Jerusalem, Israel.
Sukhotinsky
I
I
Mashriki
Y
Y
Hanani
M
M
Selinger
Z
Z
Gilon
C
C
D000818:Animals; D004220:Disulfides; D006168:Guinea Pigs; D007082:Ileum; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007769:Lactams; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000502:physiology; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D018042:Receptors, Neurokinin-3 / Q000502:physiology; D013373:Substance P / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D004220:Disulfides; D007202:Indicators and Reagents; D007769:Lactams; D019151:Peptide Library; D010456:Peptides, Cyclic; D018040:Receptors, Neurokinin-1; D018042:Receptors, Neurokinin-3; D013373:Substance P