Synthesis and opioid activity profiles of cyclic dynorphin analogs

Abstract

In an effort to reduce the conformational flexibility of the x-receptor selective opioid peptide dynorphin A, we synthesized the cyclic analogs ▪ dynorphin 5A-(1–8) ( 1 ), ▪-dynorphin A-(1–13) ( 2 ), ▪ dynorphin A-(1–13)( 3 ) and ▪ dynorphin A-(1–13). These side chain-to-side chain cyclized lactam analogs were prepared by the solid-phase method using a protection scheme which permitted cyclization of the peptide still attached to the solid support. In all four cases the desired cyclic analogs were obtained in reasonable yield. Aside from the cyclic monomers, the crude products also contained the side-chain-linked antiparallel cyclic dimer and higher oligomers which had been formed through intersite reaction on the resin. The obtained results demonstrate that cyclic lactam analogs containing relatively large ring structures (up to 31-membered) can be prepared by this method. In the guinea pig ileum assay analog 1 was 45 times more potent than linear dynorphin A-(l–8), whereas analogs 2 – 4 were 460–1,350 times less potent than linear dynorphin A-(l–l3). All four analogs showed K e-values for naloxone as antagonist below 5 nM in the latter assay, indicating that they no longer interact significantly with x-receptors. In the opioid receptor binding assays cyclic analog 1 displayed extraordinarily high affinity for the μ-receptor and the determined ratios of the binding inhibition constants ( K i δ K i μ ) indicated that all four analogs are μ-receptor selective. It is concluded that the performed cyclizations resulted in overall folded conformations which are incompatible with the conformational requirements of the x-receptor.