Novel strategies for the design of receptor-selective vasopressin analogues: Aib-substitution and retro-inverso transformation

1. We determined the pharmacological profile of novel backbone-modified peptides designed as protease-resistant, selective analogues of AVP. Binding affinities of peptides were determined at both V(1A) and V₂ subtypes of vasopressin receptor (VPR). Biological potencies of selected peptides were tested in pressor and antidiuretic bioassays. 2. Substitution of the achiral α-aminoisobutyric acid (Aib) at position 4 or 7 of AVP produced peptides that selectively bound the V₂ VPR. Both [Aib⁴]AVP (140 IU mg^-1) and [Aib⁷]AVP (36 IU mg^-1) are selective antidiuretic agonists with little or no activity in uterotonic and presser assays. 3. [AiB⁴] and [Aib⁷] derivatives of the linear V(1A)-selective antagonist [PhaaDTyr(Et)²Arg⁶Tyr(N-H₂)⁹AVP bound selectively and with high affinity (k(d) 0.51 and 4.1 nM respectively) to the V(1A) VPR. Bioassays confirmed that these peptides were potent antivasopressor agents (pA₂ 8.10 and 8.36 respectively). 4. A total retro-inverso strategy was used to prepare protease-resistant mimetics of both AVP and linear V(1A)-selective antagonists. Cyclic retro-inverso mimetics of AVP did not bind either V(1A) or V₂ VPRs. In contrast, rationally designed retro-inverso mimetics of linear V(1A)-selective antagonists selectively bound the V(1A) VPR. 5. Our findings indicate novel methods to improve the pharmacodynamic and pharmacokinetic parameters of neurohypophysial hormone analogues which could be equally applicable to other peptide-receptor systems.