Design and synthesis of highly potent and selective cyclic dynorphin A analogs

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Abstract
We have designed and synthesized several cyclic disulfide-containing peptide analogues of dynorphin A (Dyn A) which are conformationally constrainted in the putative "address" segment of the opioid ligand. Several of these Dyn A analogues exhibit unexpected selectivities for the .kappa. and .mu. opioid receptor(s) of the central vs peripheral nervous system. Thus, incorporation of conformational constraint in the putative "address" segment of Dyn A analogues has resulted in the .kappa./.mu. opioid receptor ligands [Cys5,Cys11]DynA1-11-NH2 (1) and [Cys5,Cys11,D-Ala8]Dyn A1-11-NH2 (2), which possess high .kappa. and .mu. opioid receptor affinities centrally (guinea pig brain, GPB), but only weak activity at peripheral .kappa. and .mu. opioid 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 .kappa. potencies and selectivities at the peripheral (GPI) but not at the central (GPB) .kappa. 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 .kappa. and .mu. opioid receptors of the brain and peripheral nervous systems.