Synthesis and biological activity of NK-1 selective, N-backbone cyclic analogs of the C-terminal hexapeptide of substance P

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Synthesis and biological activity of NK-1 selective, N-backbone cyclic analogs of the C-terminal hexapeptide of substance P

Year: 

1996

Source of publication :

Journal of Medicinal Chemistry

Authors :

זלצר, אירנה

.

Volume :

Co-Authors: 

Byk, G., Department of Organic Chemistry, Hebrew University of Jerusalem, Jerusalem 91904, Israel, UMR-133 CNRS/RPR, Rhône Poulenc Rorer, Ctr. de Rech. de Vitry-Alfortville, 13 Quai Jules Guesde, 94403 Vitry-sur-Seine, France
Halle, D., Department of Biological Chemistry, Hebrew University of Jerusalem, Jerusalem 91904, Israel
Zeltser, I., Department of Organic Chemistry, Hebrew University of Jerusalem, Jerusalem 91904, Israel
Bitan, G., Department of Organic Chemistry, Hebrew University of Jerusalem, Jerusalem 91904, Israel
Selinger, Z., Department of Biological Chemistry, Hebrew University of Jerusalem, Jerusalem 91904, Israel
Gilon, C., Department of Organic Chemistry, Hebrew University of Jerusalem, Jerusalem 91904, Israel

From page: 

3174

To page: 

3178

(

Total pages: 

5

)

Link :

Synthesis and biological activity of NK-1 selective, N-backbone cyclic analogs of the C-terminal hexapeptide of substance P

Abstract: 

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.