Design of potent and selective linear antagonists of vasopressor (V1-receptor) responses to vasopressin

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Abstract
We report the solid-phase synthesis of 21 linear analogues of A and D, two nonselective antagonists of the vasopressor (V1) and antidiuretic (V2) responses to arginine vasopression (AVP). A is Aaa-D-Tyr(Et)-Phe-Val-Asn-Abu-Pro-Arg-Arg-NH2 (where Aaa-adamantylacetyl at position 1). D is the des-Arg9 analogue of A. Nine new analogues of A (1-9) and 12 new analogues of D (10-21) were obtained. The following substitutions either alone or in combination were incorporated in A and/or in D: phenylacetic acid (Phaa) and tert-butylacetic acid (t-Baa) at position 1; D-Tyr2, D-Tyr(Me)2; Gln4; Arg6, Orn6, MeAla7. The nine new analogues of A are (1) [Arg6], (2) [Lys6], (3) [Orn6], (4) [Phaa1, Lys6], (5) [Phaa1,Orn6], (6) [D-Tyr2], (7) [D-Tyr2,Arg6], (8) [Phaa1,D-Tyr2], (9) [Phaa1,D,Tyr2,Arg6]. The 12 new analogues of D are (10) [Arg6], (11), [Lys6], (12) [Orn6], (13) [Phaa1,Lys6], (14) [Phaa1,Gln4,Lys6], (15) [Phaa,D-Tyr(Me)2,Lys6], (16) [Phaa,D-Tyr(Me)2,Gln4,Lys6], (17) [Phaa1,D-Tyr2,G;n4,Lys6], (18) [t-Baa1,Lys6], (19) [t-Baa1,Gln4,Lys6], (20) [Arg6,MeAla7], (21) [t-Baa1,Arg6,MeAla7]. All 21 peptides were examined for agonistic and antagonistic potencies in AVP V2 and V1 assays in rats. With the exception of 6, the eight remaining new analogues of A are equipotent or more potent than A as V1 antagonists. Peptides 2-9 are less potent than A as A2 antagonists. Three, 4, 5, and 9, exhibit significant gains in anti-V1/anti-V2 selectivities (selectivity ratio = 41, 14, and infinite, respectively), compared to A (anti-V1, pA2 = 7.75 .+-. 0.07; selectivity ratio = 0.44). Peptide 9 is unique in both series. It is a highly potent V1 antagonist (anti-V1 pA2 = 8.62 .+-. 0.11) and is the first linear peptide to exhibit substantial antidiuretic agonism (4.1 .+-. 0.2 units/mg). With the exception of 12, the remaining 11 analogues of D are 8-40 times more potent than D as V1 antagonists. Eight of these peptides exhibit significant gains in anti-V1/anti-V2 selectivities compared to D (anti-V1 pA2 = 7.43 .+-. 0.06; selectivity ratio = 1.6). Their corresponding anti-V1 pA2 values and selectivity ratios are (13) 8.81 .+-. 0.06; 26; (14) 9.05 .+-. 0.09; .apprx. 570; (15) 8.61 .+-. 0.03 .apprx. 35; (16); 8.93 .+-. 0.05; > 290; (17) 8.91 .+-. 0.04, .apprx. 59; (18) 8.63 .+-. 0.10; .apprx. 41; (19) 8.40 .+-. 0.05; > 1500; (20) 8.34 .+-. 0.06, .apprx. 53; the usefulness of a Gln4/Val4 interchange in enhancing anti-V1/anti-V2 selectivity is clearly demonstrated by the high selectivity ratios of 14, 16, and 19. With anti-V1 pA2 values of 8.6 or better, seven of these linear molecules are as potent as any cyclic V1 antagonists reported to date. Furthermore, peptides 14, 16, and 19 are as selective as or more selected than any cyclic V1 antagonists reported to date. Peptide 14 is the first AVP antagonist cyclic or linear to possess a mean pA2 value greater than 9. Many of these potent and selective linear AVP antagonists could serve as useful pharmacological tools for studies on (a) AVP receptor subtypes and (b) the putative physiological functions of AVP.