DESIGN AND SYNTHESIS OF HIGHLY POTENT AND SELECTIVE CYCLIC DYNORPHIN-A ANALOGS

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. © 1990, American Chemical Society. All rights reserved.