Design and Synthesis of Highly Potent and Selective Cyclic Dynorphin A Analogues

We have designed and synthesized several cyclic disulfide-containing peptide analogues of dynorphin A (Dyn A) which are conformationally constrained in the putative “address” segment of the opioid ligand. Several of these Dyn A analogues exhibit unexpected selectivities for the k and μ opioid receptors(s) of the central vs peripheral nervous systems. Thus, incorporation of conformational constraint in the putative “address” segment of Dyn A analogues has resulted in the k/μopioid receptor ligands [Cys⁵,Cysⁿ]Dyn A₁_₁₁-NH₂ (1) and [Cys⁵,Cys¹¹,D-Ala⁸]Dyn A₁ -1 ₁-NH₂(2), which possess high k and μ opioid receptor affinities centrally (guinea pig brain, GPB), but only weak activity at peripheral k and μopioid receptors (guinea pig ileum, GPI). On the other hand, [Cys⁸,Cys¹³]Dyn A₁_₁₃-NH₂ and [D-Cys⁸,D-Cys¹³]Dyn A₁_₁₃-NH₂ (5) display high k potenciesand selectivities at the peripheral (GPI) but not at the central (GPB) k opioid receptor. The lack of correlation between the pharmacological profiles observed in smooth muscle and in the brain binding assays suggests the existence of different subtypes of the k and μ opioid receptors in the brain and peripheral nervous systems.