INFLUENCE OF LIPOPHILICITY OIL THE BIOLOGICAL-ACTIVITY OF CYCLIC PSEUDOPEPTIDE NK-2 RECEPTOR ANTAGONISTS

A series of cyclic pseudopeptides of the formula cyclo(Leu Psi[CH2NH]X aa-Gln-Trp-Phe-beta Ala), where Xaa represents the residue of an alpha -amino acid, has been synthesized in order to establish the role of th e Xaa side chain for tachykinin NK-2 receptor antagonist activity. Syn theses have been carried out in solid phase with either Fmoc or Boc st rategy. The antagonist potency on NK-2 receptors in the hamster isolat ed trachea (HT) and the rabbit isolated pulmonary artery (RPA) bioassa ys increases with Xaa Lipophilicity; cyclo(Leu Psi[CH2NH]Cha-Gln-Trp-P he-beta Ala) and cyclo(Leu Psi[CH2NH]Asp(NHBzl)-Gln-Trp-beta Ala) resu lted in being the two most active antagonists (pA(2) = 9.06 and 9.26 o n HT, respectively). A significant linear correlation was found betwee n pA(2) values determined in HT and RPA bioassays and capacity factors measured in reversed phase HPLC. The comparison between the biologica l activities of cyclic hexapeptides containing or not containing the a minomethylene moiety proved the crucial role of the pseudopeptide bond for determining high antagonist potency at the NK-2 receptor.