title: Backbone cyclization of the C-terminal part of substance P. Part 1: The important role of the sulphur in position 11.
abstract: Novel backbone-to-side chain and backbone-to-backbone cyclic analogues of substance P (SP) were prepared by solid-phase synthesis and screened for biological activity. An analogue containing a thioetherlactam ring between positions 9 and 11 showed an EC50 value of 20 nM toward the neurokinin 1 (NK-1) and was inactive toward the NK-2 and NK-3 receptors. On the other hand, in a multiple backbone cyclic peptide library of similar analogues, in which the sulphur was excluded from the ring, very low activity was detected. The activity was re-evaluated and was found to be even lower (EC50 = 0.11 mM) than the previously published data. These results indicate that the thioether moiety has a crucial role in receptor activation. The results also show tolerance of the NK-1 receptor, but not NK-2 or NK-3, to cyclization of the C-terminal portion of the SP6-11 hexapeptide.
authors.affiliation: Department of Organic Chemistry, Hebrew University of Jerusalem, Givat-Ram, Israel.
authors.forename: G
authors.initials: G
authors.lastname: Bitan
authors.forename: I
authors.initials: I
authors.lastname: Zeltser
authors.forename: G
authors.initials: G
authors.lastname: Byk
authors.forename: D
authors.initials: D
authors.lastname: Halle
authors.forename: Y
authors.initials: Y
authors.lastname: Mashriki
authors.forename: E V
authors.initials: EV
authors.lastname: Gluhov
authors.forename: I
authors.initials: I
authors.lastname: Sukhotinsky
authors.forename: M
authors.initials: M
authors.lastname: Hanani
authors.forename: Z
authors.initials: Z
authors.lastname: Selinger
authors.forename: C
authors.initials: C
authors.lastname: Gilon
mesh_terms: D000818:Animals; D001681:Biological Assay; D003500:Cyclization; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000187:drug effects; D018041:Receptors, Neurokinin-2 / Q000187:drug effects; D018042:Receptors, Neurokinin-3 / Q000187:drug effects; D013373:Substance P / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism*; D013455:Sulfur / Q000737:chemistry / Q000502:physiology*
chemical_list: D010456:Peptides, Cyclic; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D013373:Substance P; D013455:Sulfur