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.
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-Apc(2), Val(4)]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 -Apc(2) in position 2 of either AVP or OT resulted in analogues with high antioxytocin potency. Two of the new compounds, [Mpa(1),cis-Apc(2)]AVP and [Mpa(1),cis-Apc(2),Val(4)]AVP, were exceptionally potent antiuterotonic agents (pA(2) = 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-Apc(2),Val(4)]AVP (XI) which turned out to be a moderately potent and exceptionally selective OT antagonist (pA(2) = 7.26).
Faculty of Chemistry, Institute of Organic Synthesis, University of Gdańsk, Sobieskiego 18/19, 80-952 Gdańsk, Poland. aniak@chem.univ.gda.pl
Anna
A
Kwiatkowska
Monika
M
Ptach
Lenka
L
Borovičková
Jiřina
J
Slaninová
Bernard
B
Lammek
Adam
A
Prahl
D000595:Amino Acid Sequence; D000818:Animals; D050034:Antidiuretic Agents; D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry; D003510:Cyclohexanes / Q000737:chemistry; D015195:Drug Design; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D051381:Rats; D017208:Rats, Wistar; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014662:Vasoconstrictor Agents
C506369:1-amino-4-phenylcyclohexane-1-carboxylic acid; D050034:Antidiuretic Agents; D002264:Carboxylic Acids; D003510:Cyclohexanes; C569600:OXTR protein, human; D018045:Receptors, Oxytocin; D014662:Vasoconstrictor Agents; D001127:Arginine Vasopressin; D010121:Oxytocin