Design, synthesis and biological activity of new neurohypophyseal hormones analogues conformationally restricted in the N-terminal part of the molecule. Highly potent OT receptor antagonists

Anna Kwiatkowska , Monika Ptach , Lenka Borovičková , Jiřina Slaninová , Bernard Lammek , Adam Prahl

Abstract

In this study we present the synthesis and some pharmacological properties of fourteen new analogues of neurohypophyseal hormones conformationally restricted in the N-terminal part of the molecule. All new peptides were substituted at position 2 with cis-1-amino-4-phenylcyclohexane-1-carboxylic acid (cis-Apc). Moreover, one of the new analogues: [cis-Apc2, Val4]AVP was also prepared in N-acylated forms with various bulky acyl groups. All the peptides were tested for pressor, antidiuretic, and in vitro uterotonic activities. We also determined the binding affinity of the selected compounds to human OT receptor. Our results showed that introduction of cis -Apc2 in position 2 of either AVP or OT resulted in analogues with high antioxytocin potency. Two of the new compounds, [Mpa1,cis-Apc2]AVP and [Mpa1,cis-Apc2,Val4]AVP, were exceptionally potent antiuterotonic agents (pA2 = 8.46 and 8.40, respectively) and exhibited higher affinities for the human OT receptor than Atosiban (K i values 5.4 and 9.1 nM). Moreover, we have demonstrated for the first time that N -terminal acylation of AVP analogue can improve its selectivity. Using this approach, we obtained compound Aba[cis-Apc2,Val4]AVP (XI) which turned out to be a moderately potent and exceptionally selective OT antagonist (pA2 = 7.26).
Author Anna Kwiatkowska (FCh / DOCh)
Anna Kwiatkowska,,
- Department of Organic Chemistry
, Monika Ptach (FCh / DOCh)
Monika Ptach,,
- Department of Organic Chemistry
, Lenka Borovičková
Lenka Borovičková,,
-
, Jiřina Slaninová
Jiřina Slaninová,,
-
, Bernard Lammek (FCh / DOCh / LChB)
Bernard Lammek,,
- Laboratory of Chemistry of Biopolymers
, Adam Prahl (FCh / DOCh / LChB)
Adam Prahl,,
- Laboratory of Chemistry of Biopolymers
Journal seriesAmino Acids, ISSN 0939-4451, (A 25 pkt)
Issue year2012
Vol43
No2
Pages617-627
Publication size in sheets0.5
Keywords in Englishoxytocin antagonists, atosiban, neurohypophyseal hormones analogues, arginine vasopressin (AVP), antidiuretic hormone, binding affinity
DOIDOI:10.1007/s00726-011-1109-6
URL http://www.springerlink.com/content/25477k86t63w2636/fulltext.pdf
Languageen angielski
Score (nominal)30
Publication indicators WoS Impact Factor: 2012 = 3.914 (2) - 2012=3.742 (5)
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