Vasopressin Analog with Extraordinarily High Antidiuretic Potency: A Study of Conformation and Activity

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Abstract
Application of information derived from a three-dimensional model of vasopressin bound to its antidiuretic receptor has resulted in the design and synthesis of a potent analog, [1-deamino,2-phenylalanine,7-(3,4-dehydroproline)]-arginine vasopressin; this analog has a specific antidiuretic activity of 13,000 ± 1,250 units per milligram; noteworthy at these doses is the absence of any detectable pressor activity. Three modifications based on conformational considerations were introduced into the vasopressin molecule in preparing the analog: (i) to enhance binding, a double bond was introduced into the side chain of an amino acid residue occupying a corner position of a β turn in the vasopressin conformation, (ii) the hydroxyl moiety was deleted from Tyr 2 , and (iii) to tighten the backbone structure and to enhance the enzymatic resistance of the analog, the NH 2 -terminal amino group was deleted.