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

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 V 2 subtypes of vasopressin receptor (VPR). Biological potencies of selected peptides were tested in pressor and antidiuretic bioassays. Substitution of the achiral α‐aminoisobutyric acid (Aib) at position 4 or 7 of AVP produced peptides that selectively bound the V 2 VPR. Both [Aib 4 ]AVP (140 IU mg −1 ) and [Aib 7 ]AVP (36 IU mg −1 ) are selective antidiuretic agonists with little or no activity in uterotonic and pressor assays. [Aib 4 ] and [Aib 7 ] derivatives of the linear V 1A ‐selective antagonist [PhaaDTyr(Et) 2 Arg 6 Tyr(NH 2 ) 9 ]AVP bound selectively and with high affinity ( K d 0.51 and 4.1 n M respectively) to the V 1A VPR. Bioassays confirmed that these peptides were potent antivasopressor agents (pA 2 8.10 and 8.36 respectively). 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 V 2 VPRs. In contrast, rationally designed retro‐inverso mimetics of linear V 1A ‐selective antagonists selectively bound the V 1A VPR. 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.British Journal of Pharmacology (1999) 128 , 647–652; doi: 10.1038/sj.bjp.0702857