Conformation-activity relationship of tachykinin neurokinin A(4-10) and of some [Xaa8] analogs

Abstract

NKA (4-10), the C-terminal heptapeptide fragment (Asp-Ser-Phe-Val-Gly-Leu-Met-NH2) of tachykinin NKA, is more active than the parent native compound in the interaction with the NK-2 receptor. Substitution of Gly8 with the more flexible residue beta-Ala8 increases its selectivity with respect to other two known receptors (NK-1 and NK-3), whereas substitution with either D-Ala8 or GABA8 deprives the peptide of its biological activity. These findings can be interpreted by a conformational analysis based on NMR studies in DMSO-d6 and in a DMSO-d6/H2O cryoprotective mixture combined with internal energy calculations. NKA(4-10) is characterized by a structure containing a type I beta-turn extending from Ser5 to Gly8, followed by a gamma-turn centered on Gly8, whereas for [beta-Ala8]NKA(4-10) is possible to suggest a type I beta-turn extending from Ser5 to beta-Ala8, followed by a C8 turn comprising beta-Ala8 and Leu9 and by another beta-turn extending from beta-Ala8 to the terminal NH2. The preferred conformation of [beta-Ala8]NKA(4-10) is not compatible with models for NK-1 and NK-3 agonists proposed on the basis of rigid peptide agonists [Levian-Teitelbaum et al. (1989) Biopolymers 28, 51-64; Sumner & Ferretti (1989) FEBS Lett. 253, 117-120]. The preferred solution conformation of [beta-Ala8]NKA(4-10) may thus be considered as a likely bioactive conformation for NK-2 selective peptides.