Potent antagonists of the antidiuretic responses to arginine-vasopressin based on modifications of [1-(.beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid),2-D-phenylalanine,4-valine]arginine-vasopressin at position four

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Abstract
As part of a program in which the structural features at positions 1-9 in previously reported antidiuretic antagonists required for antidiuretic antagonism were delineated and analogs with enhanced antiantidiuretic potency and/or selectivity were obtained, 14 new analogs of the antidiuretic antagonist [1-(.beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid),2-D-phenylalanine,4-valine]arginine-vasopressin [d-(CH2)5-D-Phe2VAVP were synthesized, in which the valine residue at position 4 was replaced by the following L-amino acids and glycine: Ile, Abu, Thr, Ala, Gln, Lys, Cha, Nle, Nva, Phe, Leu, Gly, Tyr and Pro. These analogs are 1, d-(CH2)5-D-Phe2,Ile4AVP; 2, d(CH2)5-D-Phe2,Abu4AVP; 3, d(CH2)5-D-Phe2,Thr4AVP; 4, d(CH2)5-D-Phe2,Ala4AVP; 5, d(CH2)5-D-Phe2AVP; 6, d(CH2)5-D-Phe2,Lys4AVP; 7, d(CH2)5-D-Phe2,Cha4AVP; 8, d(CH2)5-D-Phe2,Nle4AVP; 9, d(CH2)5-D-Phe2,Nva4AVP; 10, d(CH2)5-D-Phe2,Phe4AVP; 11, d(CH2)5-D-Phe2,Leu4AVP; 12, d(CH2)5-D-Phe2,Gly4AVP; 13, d(CH2)5-D-Phe2,Tyr4AVP; 14; d(CH2)5-D-Phe2,Pro4AVP. The protected intermediates required for the synthesis of all of these peptides were prepared by the solid-phase method and cleaved from the resin by ammonolysis. Following deblocking with Na in NH3 and oxidizing with K3[Fe(CN)6], each peptide was purified on Sephadex G-15 in a 2-step procedure using 50% HOAc and 0.2 M HOAc as eluants. Analogs 1-14 were tested for agonistic and antagonistic activities by antidiuretic, vasopressor and oxytocic assays in rats. Analogs 1, 2 and 4-6 exhibit no detectable antidiuretic agonistic activity. All analogs, with the exception of the Pro4-containing analog, are antidiuretic antagonists. Their antiantidiuretic pA2 values are as follows: 1, 8.24 .+-. 0.08; 2, 7.96 .+-. 0.07; 3 7.62 .+-. 0.09; 4, 7.52 .+-. 0.03; 5, 7.21 .+-. 0.07; 6, 7.22 .+-. 0.12; 7, 7.19 .+-. 0.08; 8, 7.12 .+-. 0.09; 9, 6.99 .+-. 0.06; 10, 6.07 .+-. 0.11; 11, 6.07 .+-. 0.11; 12, 5.85 .+-. 0.05; 13, .apprx. 5.57; 14, a weak agonist (0.004 U/mg). Analogs 1-14 also antagonize the vascular responses to AVP and the in vitro oxytocic responses to oxytocin. Analogs, 1, 2, 3 and 5 have also been shown to antagonize the in vivo oxytocic responses to oxytocin. Five of these analogs (1, 2, 3, 6 and 7) exhibit enhanced antiantidiuretic/antivasopressor selectivity. d(CH2)5-D-Phe2,Lys4AVP and other position-4 analogs with side-chain functional groups may be useful covalent ligands with which to probe the structural characteristics of AVP renal and vascular receptors. With an antiantidiuretic effective dose of 0.46 .+-. 0.07 nmol/kg and a pA2 value of 8.24 .+-. 0.08, d(CH2)5-D-Phe2,Ile4AVP (1) appears to be the most potent antidiuretic antagonist reported to date. This and some of the other analogs reported here should prove to be useful pharmacological tools for studies on the role(s) of AVP in the etiology of water retention states and may also be of value as therapeutic agents for the treatment of such conditions in humans. These findings also provide valuable insights for the design of more potent and selective antidiuretic antagonists.