Collect. Czech. Chem. Commun. 1988, 53, 2617-2626

2-O-methyl and 2-O-ethyl-tyrosine derivatives of [8-arginine]vasopressin analogs: Highly specific antidiuretic agonists

Krzysztof Bankowskia, Bernard Lammekb, Marian Kruszynskib, Maurice Manningc, Janny Setod and Wilbur H. Sawyerd

a Department of Chemistry, University of Warsaw, 02-093 Warsaw, Poland
b Institute of Chemistry, University of Gdańsk, 80-952 Gdansk, Poland
c Department of Biochemistry, Medical College of Ohio, Toledo, Ohio 43699, U.S.A.
d Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York 10032, U.S.A.


The solid phase synthesis of seven 2-O-methyl- and 2-O-ethyl-tyrosine substituted analogs of [8-arginine]vasopressin (AVP) with enhanced antidiuretic agonistic specificity is reported. These peptides are: [2-O-ethyltyrosine, 8-arginine]vasopressin (I), [2-O-methyltyrosine, 8-D-arginine]vasopressin (II), [2-O-ethyltyrosine, 8-D-arginine]vasopressin (III), [2-O-methyltyrosine, 4-valine, 8-arginine]vasopressin (IV), [2-O-ethyltyrosine, 4-valine, 8-arginine]vasopressin (V), [2-O-methyltyrosine, 4-valine, 8-D-arginine]vasopressin (VI), [2-O-ethyltyrosine, 4-valine, 8-D-arginine]vasopressin (VII). All analogs were tested for antidiuretic, antivasopressor and antioxytocic activities. Although all these new analogs are antidiuretic agonists they are antagonists of vasopressor responses to AVP, and of responses by the rat uterus to oxytocin. Thus, all seven new Tyr(Me) and Tyr(Et) containing analogs exhibit high antidiuretic specificity and have infinite antidiuretic/pressor (A/P) and antidiuretic/oxytocic (A/O) activity ratios. Some of these analogs e.g. Tyr(Me)DAVP, Tyr(Me)VAVP and Tyr(Me)VDAVP, which possess high antidiuretic activity with no pressor or oxytocic agonism, could be useful new pharmacological tools for characterizing receptors mediating specific responses to the neurohypophyseal hormones. They could also be potentially useful in the treatment of diabetes insipidus.