Synthesis and biological activity of NK-1 selective, N-backbone cyclic analogs of the C-terminal hexapeptide of substance P.
The application of the concept of backbone cyclization to linear substance P (SP) analogs is presented. We describe the synthesis, characterization, and biological activity of a series of backbone-to-amino-terminus cyclic analogs of the C-terminal hexapeptide of SP. These analogs were designed on the basis of NMR data and molecular modeling of the selective NK-1 analog WS-septide (Ac[Arg6,Pro9]SP6-11). A series of peptides with the general formula: cyclo[-CH2)m-NH-CO-(CH2)n-CO-Arg-Phe-Phe-N-]-CH2-CO-Leu-Met-NH2 (n = 2, 3, 6 and m = 2, 3, 4) was synthesized by solid phase methodology using Fmoc chemistry for the main chain and Boc chemistry for the building units [Na-(omega-aminoalkyl)Gly] side chains. Cyclization was performed on the resin after removal of the Boc protecting group from the omega-aminoalkyl chain. Cyclic and precyclic analogs were compared. They were purified by HPLC and characterized by mass spectroscopy and NMR. Biological activity and selectivity to the NK-1 neurokinin receptor were found to depend on cyclization and the ring size: The most active and selective analog had a ring of 20 atoms. This analog was found to have enhanced metabolic stability in various tissue preparation compared to WS-septide.
Byk
G
G
Department of Organic Chemistry, Hebrew University of Jerusalem, Israel.
Halle
D
D
Zeltser
I
I
Bitan
G
G
Selinger
Z
Z
Gilon
C
C
D000595:Amino Acid Sequence; D000818:Animals; D006168:Guinea Pigs; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000187:drug effects; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013373:Substance P / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D010446:Peptide Fragments; D010456:Peptides, Cyclic; D018040:Receptors, Neurokinin-1; D013373:Substance P; C032292:substance P (6-11); D011761:Pyrrolidonecarboxylic Acid