SYNTHESIS AND PHARMACOLOGICAL PROPERTIES OF [2-ISOLEUCINE]-8-LYSINE-VASOPRESSIN AND ITS 1-DEAMINO ANALOG

[2-Isoleucine]-8-lysine-vasopressin, an analog of the pressor antidiuretic hormone in which the tyrosine residue is replaced by an isoleucine residue, has been synthesized and tested for pharmacological activity. This analog was prepared by synthesis of the required nonapeptide intermediate by the stepwise p-nitrophenyl ester method. Reduction of this protected nonapeptide with sodium in liquid ammonia and oxidation of the resulting dithiol with potassium ferricyanide yielded the [2-isoleucine]-8-lysine-vasopressin, which was then purified by partition chromatography and gel filtration on Sephadex G-25. [2-Isoleucine]-8-lysine-vasopressin was found to possess about 0.5 unit/mg of avian vasodepressor activity, less than 0.005 unit/mg of oxytocic activity, about 1.8 units/mg of pressor activity, and 3.7 units/mg of antidiuretic activity. [1-β-Mercaptopropionic acid,2-isoleucine]-8-lysine-vasopressin, in which the free amino group on the half-cystine residue at position 1 of [2-isoleucine]-8-lysine-vaso-pressin is replaced by hydrogen, was also prepared in a similar manner. It was found to possess about 1.0 unit mg of avian vasodepressor activity, less than 0.1 unit/mg of oxytocic activity, about 1.5 units/mg of pressor activity, and about 3.0 units/mg of antidiuretic activity. Thus both analogs possessed extremely low pharmacological activities in contrast to comparable analogs of oxytocin, which exhibited an appreciable degree of oxytocic, avian vasodepressor, and milk-ejecting activity. © 1969, American Chemical Society. All rights reserved.