Conformations and Receptor Activity of Desmopressin Analogues, Which Contain -Turn Mimetics or a [CH2O] Isostere

• Three analogues of the antidiuretic drug desmopressin ([1-desamino,8-D-arginine]vasopressin) have been prepared. In two of these, -turn mimetics based on a morpholin-3-one framework have been inserted instead of residues Phe3-Asn5, whereas the third analogue has a methylene ether isostere in place of the amide bond between residues 3 and 4. The three analogues were used to probe if the structure determined for desmopressin in aqueous solution, which contains an inverse -turn centered around Gln4, is important in interactions with the vasopressin V2 receptor. Conformational studies revealed that the analogues that contain either an inverse -turn mimetic or a methylene ether isostere mimicked the conformation of desmopressin fairly well and very well, respectively. Despite this, the analogues displayed only very low agonistic activities at the vasopressin V2 receptor. Consequently, an inverse -turn involving residues Phe3-Asn5 does not appear to be important when desmopressin is bound to the V2 receptor. In addition, it was concluded that the amide bond between Phe3 and Gln4 in desmopressin is crucial for interactions with the antidiuretic V2 receptor.

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