Conformations and receptor activity of desmopressin analogues, which contain gamma-turn mimetics or a psi[CH(2)O] isostere.
Three analogues of the antidiuretic drug desmopressin ([1-desamino,8-D-arginine]vasopressin) have been prepared. In two of these, gamma-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 gamma-turn centered around Gln4, is important in interactions with the vasopressin V(2) receptor. Conformational studies revealed that the analogues that contain either an inverse gamma-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 V(2) receptor. Consequently, an inverse gamma-turn involving residues Phe3-Asn5 does not appear to be important when desmopressin is bound to the V(2) receptor. In addition, it was concluded that the amide bond between Phe3 and Gln4 in desmopressin is crucial for interactions with the antidiuretic V(2) receptor.
Hedenström
Mattias
M
Organic Chemistry, Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
Yuan
ZhongQing
Z
Brickmann
Kay
K
Carlsson
Jolanta
J
Ekholm
Kjell
K
Johansson
Birgitta
B
Kreutz
Eva
E
Nilsson
Anders
A
Sethson
Ingmar
I
Kihlberg
Jan
J
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D003894:Deamino Arginine Vasopressin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004231:Diuresis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018716:Molecular Mimicry; D017433:Protein Structure, Secondary; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000819:agonists / Q000187:drug effects*; D012076:Renal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D065092:Antidiuretic Hormone Receptor Antagonists; D017483:Receptors, Vasopressin; D012076:Renal Agents; D003894:Deamino Arginine Vasopressin