Importance of the aromatic residue at position 6 of [Nle(10)]neurokinin A(4-10) for binding to the NK-2 receptor and receptor activation.
Steric and electrostatic requirements at position 6 of [Nle(10)]NKA(4-10), a full agonist of NK-2 receptors, for molecular recognition by the receptor were studied. Two series of peptide analogues, (a) p-substituted analogues, [p-X-Phe(6), Nle(10)]NKA(4-10), where X = F, Cl, Br, I, NH(2), NO(2), and (b) [D-Phe(6),Nle(10)]NKA(4-10), [Trp(6),Nle(10)]NKA(4-10), and [Chex-Ala(6),Nle(10)]NKA(4-10), were synthesized, and their biological activity was examined. Competition binding experiments with [(3)H]NKA were performed using cloned human NK-2 receptors expressed in CHO cells. Antagonistic and agonistic properties of the analogues were studied using an in vitro functional assay with hamster tracheal rings. The rank order of potency of agonists was [Nle(10)]NKA(4-10) approximately [p-F-Phe(6),Nle(10)]NKA(4-10) > [p-NH(2)-Phe(6),Nle(10)]NKA(4-10) > [p-Cl-Phe(6),Nle(10)]NKA(4-10) > [p-NO(2)-Phe(6),Nle(10)]NKA(4-10) > [Trp(6),Nle(10)]NKA(4-10). Size and planarity of the aromatic side chain were crucially important for the biological activity, whereas electron-donating and electron-withdrawing properties of the para-substituent were less important. The results favor the hypothesis that weakly polar pi-pi interactions exist between the aromatic group and the receptor.
Gembitsky
D S
DS
Department of Biomedical Sciences, Creighton University School of Medicine, 2500 California Plaza, Omaha, Nebraska 68178-0405, USA.
Murnin
M
M
Otvös
F L
FL
Allen
J
J
Murphy
R F
RF
Lovas
S
S
D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008647:Mesocricetus; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D015288:Neurokinin A / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000819:agonists* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D010446:Peptide Fragments; D018041:Receptors, Neurokinin-2; C061060:neurokinin A (4-10), Nle(10)-; D015288:Neurokinin A