Cyclic analogues of dynorphin A-(1-13) amide (Dyn A-(1-13)NH2) were synthesized and their opioid receptor affinity and opioid activity determined. Cyclic peptides constrained in both the "message" and "address" regions of Dyn A-(1-13)NH2 (1) were prepared in order to investigate possible biological conformations of different regions of the peptides. The design of the constraint was based upon Schwyzer's proposal that Dyn A-(1-13) adopts an α-helix when it binds to κ opioid receptors in the lipid membrane (2). Molecular modeling with AMBER suggested that a four atom bridge between the α carbons of residues i (D-configuration) and i + 3 (L-configuration) may be compatible with a helical structure. Therefore we synthesized a series of cyclo[D-Aspi,Dapi+3]Dyn A-(1-13)NH2 analogues (Dap = α,β-diaminopropionic acid) with the lactam bridge between noncritical residues 2 and 5, 3 and 6, 5 and 8, or 6 and 9. Of these cyclic peptides, the [2,5] cyclic analogue exhibited the highest opioid receptor affinity and opioid activity.
All Science Journal Classification (ASJC) codes
- Clinical Biochemistry
- Cellular and Molecular Neuroscience