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Synthesis and some pharmacological properties of 18 potent O-alkyltyrosine-substituted antagonists of the vasopressor responses to arginine-vasopressin. 1985

M Manning, and B Lammek, and K Bankowski, and J Seto, and W H Sawyer

Using the Merrifield solid-phase method, we have synthesized 18 new 2-O-alkyltyrosine-substituted analogues (where alkyl = methyl and ethyl) of the arginine-vasopressin (AVP) vasopressor antagonists [1-deaminopenicillamine]-arginine-vasopressin (dPAVP), [1-(beta-mercapto-beta,beta-diethylpropionic acid)]arginine-vasopressin (dEt2AVP), and [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid)]arginine-vasopressin (d(CH2)5AVP) and of their 8-D-arginine (d(R2)DAVP) analogues, their 4-valine (dR2VAVP) analogues, and their 4-valine,8-D-arginine (d(R2)VDAVP) analogues [where R = CH3 or C2H5 and 2R = (CH2)5]. These analogues were tested for agonistic and antagonistic activities in in vivo rat vasopressor and rat antidiuretic and in vitro rat uterus assay systems. Although many exhibit very low antidiuretic activities, none of the new analogues antagonize antidiuretic responses to AVP. They exhibit no evident pressor activities and are in fact all highly effective antagonists of the vasopressor responses to AVP. They are also potent antagonists of the in vitro oxytocic responses to oxytocin, both in the absence and in the presence of Mg2+. These analogues together with their corresponding antivasopressor pA2 values are as follows: 1. dPTyr(Et)AVP, 8.40 +/- 0.08; 2. dEt2Tyr(Me)AVP, 8.53 +/- 0.06; 3. dEt2Tyr(Et)AVP, 8.46 +/- 0.08; 4. d(CH2)5Tyr(Et)AVP, 8.47 +/- 0.04; 5. dPTyr(Me)DAVP, 8.31 +/- 0.08; 6. dPTyr(Et)DAVP, 8.27 +/- 0.06; 7. dEt2Tyr(Me)DAVP, 8.57 +/- 0.03; 8. dEt2Tyr(Et)DAVP, 8.33 +/- 0.06; 9. d(CH2)5Tyr(Me)DAVP, 8.41 +/- 0.05; 10. d(CH2)5Tyr(Et)DAVP, 8.45 +/- 0.05; 11. dPTyr(Me)VAVP, 8.36 +/- 0.07; 12. dPTyr(Et)VAVP, 8.07 +/- 0.13; 13. dEt2Tyr(Me)VAVP, 8.29 +/- 0.08; 14. dEt2Tyr(Et)VAVP, 8.42 +/- 0.06; 15. dPTyr(Me)VDAVP, 7.84 +/- 0.06; 16. dPTyr(Et)VDAVP, 8.46 +/- 0.03; 17. dET2Tyr(Me)VDAVP, 8.35 +/- 0.10; 18. dEt2Tyr (Et)VDAVP, 8.19 +/- 0.07. Seven of these analogues are clearly more potent vasopressor antagonists than their respective unalkylated tyrosine-containing parents. In the remaining 11, antagonistic potency was not changed significantly. In no instance did 2-O-alkyltyrosine substitution decrease antagonistic potency. With pA2 values equal to or greater than 8.40, nine of these antagonists (numbers 1-4, 7, 9, 10, 14, and 16) are among the most potent vasopressor antagonists reported to date. They could thus serve as additional valuable pharmacological tools in studies on the roles of AVP in the control of blood pressure in normal and in pathophysiological conditions. These findings may also provide useful clues to the design of more potent and selective antagonists of AVP.

UI MeSH Term Description Entries
D010121 Oxytocin A nonapeptide hormone released from the neurohypophysis (PITUITARY GLAND, POSTERIOR). It differs from VASOPRESSIN by two amino acids at residues 3 and 8. Oxytocin acts on SMOOTH MUSCLE CELLS, such as causing UTERINE CONTRACTIONS and MILK EJECTION. Ocytocin,Pitocin,Syntocinon
D010456 Peptides, Cyclic Peptides whose amino acid residues are linked together forming a circular chain. Some of them are ANTI-INFECTIVE AGENTS; some are biosynthesized non-ribosomally (PEPTIDE BIOSYNTHESIS, NON-RIBOSOMAL). Circular Peptide,Cyclic Peptide,Cyclic Peptides,Cyclopeptide,Orbitide,Circular Peptides,Cyclopeptides,Orbitides,Peptide, Circular,Peptide, Cyclic,Peptides, Circular
D001794 Blood Pressure PRESSURE of the BLOOD on the ARTERIES and other BLOOD VESSELS. Systolic Pressure,Diastolic Pressure,Pulse Pressure,Pressure, Blood,Pressure, Diastolic,Pressure, Pulse,Pressure, Systolic,Pressures, Systolic
D002627 Chemistry, Physical The study of CHEMICAL PHENOMENA and processes in terms of the underlying PHYSICAL PHENOMENA and processes. Physical Chemistry,Chemistries, Physical,Physical Chemistries
D004231 Diuresis An increase in the excretion of URINE. (McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed) Diureses
D005260 Female Females
D000478 Alkylation The covalent bonding of an alkyl group to an organic compound. It can occur by a simple addition reaction or by substitution of another functional group. Alkylations
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001127 Arginine Vasopressin The predominant form of mammalian antidiuretic hormone. It is a nonapeptide containing an ARGININE at residue 8 and two disulfide-linked cysteines at residues of 1 and 6. Arg-vasopressin is used to treat DIABETES INSIPIDUS or to improve vasomotor tone and BLOOD PRESSURE. Argipressin,Vasopressin, Arginine,Arg-Vasopressin,Argipressin Tannate,Arg Vasopressin
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships

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