Synthesis and Biological Activity of NK-1 Selective, N-Backbone Cyclic Analogs of the C-Terminal Hexapeptide of Substance P

• Published in: Journal of medicinal chemistry Vol. 39; no. 16; pp. 3174 - 3178
• Main Authors: Byk, Gerardo, Halle, David, Zeltser, Irena, Bitan, Gal, Selinger, Zvi, Gilon, Chaim
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 02.08.1996; Amer Chemical Soc
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Chemistry, Medicinal; Guinea Pigs; Life Sciences & Biomedicine; Medical sciences; Molecular Sequence Data; Muscle, Smooth - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptide Fragments - chemical synthesis; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - metabolism; Peptides, Cyclic - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Binding; Protein Conformation; Pyrrolidonecarboxylic Acid - analogs & derivatives; Rats; Receptors, Neurokinin-1 - agonists; Receptors, Neurokinin-1 - metabolism; Science & Technology; Structure-Activity Relationship; Substance P - chemical synthesis; Substance P - chemistry; Substance P - pharmacology; RECEPTOR; NMR; PEPTIDES; CONFORMATION; NEUROKININ-B; Stability; Peptides; In vitro; Hexapeptide; Macrocycle; C terminal-Sequence; Cyclization; Structure activity relation; Carboxamide; Peptide synthesis; Solid phase; Tachykinin receptor; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960154i

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 [N α-(ω-aminoalkyl)Gly] side chains. Cyclization was performed on the resin after removal of the Boc protecting group from the ω-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.