Document Detail

Design and synthesis of potent in vivo antagonists of oxytocin.
MedLine Citation:
PMID:  7216614     Owner:  NLM     Status:  MEDLINE    
We have previously shown that the substitution of 8-ornithine and 2-O-methyltyrosine alone and in combination in [1-deaminopenicillamine] oxytocin (dPOT) brought about enhancements in antagonistic potencies to responses to oxytocin in vivo. To explore the effects of these substitutions in analogs of dPOT containing larger alkyl substitutents on the beta carbon at position 1 and on the tyrosine residue at position two, the following six analogs were synthesized: [1-(beta-mercapto-beta, beta-diethylpropionic acid), 8-ornithine] vasotocin (1, dEt2OVT); (1-beta-mercapto-beta, beta-cyclopentamethylenepropionic acid), 8-ornithine] vasotocin (2, d(CH2)5OVT): [1-beta-mercapto-beta, beta-diethylpropionic acid), 2-O-methyltyrosine, 8-ornithine]vasotocin [3, dEt2 Tyr(Me)OVT]; [1-(beta-mercapto-beta, beta-diethylpropionic acid), 2-O-ethyltyrosine, 8-ornithine]vasotocin [4, dEt2 Tyr(Et)OVT]; [1-beta-mercapto-beta', beta-cyclopentamethylenepropionic acid), 2-O-methyltyrosine, 8-ornithine]vasotocin [5, d(CH2)5 Tyr(me)OVT]: [1-beta-mercapto-beta, beta-cyclopentamethylenepropionic acid), 2-O-methyltyrosine, 8-ornithine]vasotocin [6,d(CH2)5 Tyr(Et)OVT]. The required protected intermediates were synthesized by a combination of solid-phase synthesis and by individual 8 + 1 couplings in solution. All six analogs antagonize the actions of oxytocin on the rat uterus in the absence of Mg2+, in the presence of 0.5 mM Mg2+ and in situ. They also antagonize milk ejection responses to oxytocin, and the vasopressor responses to arginine vasopressin, and all have very low antidiuretic activities. With pA2 values of 7.35 +/- 0.08 and 7.37 +/- 0.17, respectively, compounds 3 and 5 are the two most potent in vivo antagonists of oxytocin reported to date.
K Bankowski; M Manning; J Seto; J Haldar; W H Sawyer
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  International journal of peptide and protein research     Volume:  16     ISSN:  0367-8377     ISO Abbreviation:  Int. J. Pept. Protein Res.     Publication Date:  1980 Nov 
Date Detail:
Created Date:  1981-06-13     Completed Date:  1981-06-13     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0330420     Medline TA:  Int J Pept Protein Res     Country:  DENMARK    
Other Details:
Languages:  eng     Pagination:  382-91     Citation Subset:  IM    
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MeSH Terms
Amino Acid Sequence
Biological Assay
Oxytocin / antagonists & inhibitors*
Grant Support
Reg. No./Substance:

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