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 pept ides designed as protease-resistant, selective analogues of AVP. Binding af finities of peptides were determined at both V-1A and V-2 subtypes of vasop ressin receptor (VPR). Biological potencies of selected peptides were teste d in presser and antidiuretic bioassays. 2 Substitution of the achiral alpha-aminoisobutyric acid (Aib) at position 4 or 7 of AVP produced peptides that selectively bound the V-2 VPR. Both [A ib(4)]AVP (140 IU mg(-1)) and [Aib(7)]AVP (36 IU mg(-1)) are selective anti diuretic agonists with little or no activity in uterotonic and presser assa ys. 3 [Aib(4)] and [Aib(7)] derivatives of the linear V-1A-selective antagonist [PhaaDTyr(Et)(2)Arg(6)Tyr(N-H-2)(9)]AVP bound selectively and with high af finity (K-d 0.51 and 4.1 nM respectively) to the V-1A VPR. Bioassays confir med that these peptides were potent antivasopressor agents (pA(2) 8.10 and 8.36 respectively). 4 A total retro-inverso strategy was used to prepare protease-resistant mim etics of both AVP and linear V-1A-selective antagonists. Cyclic retro-inver so mimetics of AVP did not bind either V-1A or V-2 VPRs. In contrast, ratio nally 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 ph armacokinetic parameters of neurohypophysial hormone analogues which could be equally applicable to other peptide-receptor systems.