TY - JOUR
T1 - Comparison of the Conformation of Active and Nonactive Backbone Cyclic Analogs of Substance P as a Tool To Elucidate Features of the Bioactive Conformation
T2 - NMR and Molecular Dynamics in DMSO and Water
AU - Grdadolnik, Simona Golic
AU - Mierke, Dale F.
AU - Byk, Gerardo
AU - Zeltser, Irena
AU - Gilon, Chaim
AU - Kessler, Horst
PY - 1994/7/8
Y1 - 1994/7/8
N2 - The conformations of two backbone-cyclized substance P analogs as derived from 1H NMR and molecular dynamics simulations carried out in DMSO and water are described. The method of floating chiralities is used in the simulations to facilitate the diastereotopic assignment of methylene protons. One of the analogs, cyclo-[-(CH2)3-NH-CO-(CH2)4-Arg-Phe-Phe-N-]-CH2-CO-Leu-Met-NH2, is a highly active, selective agonist for the NK-receptor, while the other, cyclo[-(CH2)2-NH-CO-(CH2)2-Gly-Arg-Phe-Phe-N-]-CH2-CO-Leu-Met-NH2, is inactive. Both analogs contain cyclic ring systems of the same size, varying in only the number of amide linkages. From the conformational analysis, the lack of activity can be attributed to the introduction of too much constraint into the ring system. This has an effect on the topological array of the important residues Arg-Phe-Phe. The results presented here are compared with biologically active analogs previously examined. The differences between conformations of active and inactive compounds are used to develop insight into the conformational requirements for biological activity.
AB - The conformations of two backbone-cyclized substance P analogs as derived from 1H NMR and molecular dynamics simulations carried out in DMSO and water are described. The method of floating chiralities is used in the simulations to facilitate the diastereotopic assignment of methylene protons. One of the analogs, cyclo-[-(CH2)3-NH-CO-(CH2)4-Arg-Phe-Phe-N-]-CH2-CO-Leu-Met-NH2, is a highly active, selective agonist for the NK-receptor, while the other, cyclo[-(CH2)2-NH-CO-(CH2)2-Gly-Arg-Phe-Phe-N-]-CH2-CO-Leu-Met-NH2, is inactive. Both analogs contain cyclic ring systems of the same size, varying in only the number of amide linkages. From the conformational analysis, the lack of activity can be attributed to the introduction of too much constraint into the ring system. This has an effect on the topological array of the important residues Arg-Phe-Phe. The results presented here are compared with biologically active analogs previously examined. The differences between conformations of active and inactive compounds are used to develop insight into the conformational requirements for biological activity.
UR - http://www.scopus.com/inward/record.url?scp=0028340334&partnerID=8YFLogxK
U2 - 10.1021/jm00040a005
DO - 10.1021/jm00040a005
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C2 - 7518522
AN - SCOPUS:0028340334
SN - 0022-2623
VL - 37
SP - 2145
EP - 2152
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 14
ER -