TETRAPEPTIDE TACHYKININ ANTAGONISTS - SYNTHESIS AND MODULATION OF THEPHYSICOCHEMICAL AND PHARMACOLOGICAL PROPERTIES OF A NEW SERIES OF PARTIALLY CYCLIC ANALOGS

We report on the synthesis and the pharmacological properties of a new series of tachykinin antagonists based on the pseudopeptide pharmacop hore cyclo[-Abo-Asp(D-Trp-Phe-N(Me)Bzl)-] which contains the 2-azabicy clo[2.2.2]octane-3(S)-carboxylic acid (Abo) residue. Variation of the substituents on the tryptophan indole nitrogen was shown to modulate w ater solubility and transport properties of the analogs as well as pot ency in classical in vitro response and binding assays. One water-solu ble compound, 16, in which the substituent was 3-carbonylpropionate, s trongly prolonged the reaction time in the mouse hot-plate test both a fter iv or oral administration and was devoid of degranulating activit y in rat peritoneal mast cells.