A novel N-terminal cyclic dynorphin A analogue cyclo(N,5)[Trp(3),Trp(4),Glu(5)] dynorphin A-(1-11)NH(2) that lacks the basic N-terminus.

A novel N-terminal-to-side chain cyclic dynorphin A analogue lacking the basic N-terminus was designed based on Ac[Lys(2),Trp(3),Trp(4),d-Ala(8)]dynorphin A-(1-11)NH(2) (Wan et al. J. Med. Chem. 1999, 42, 3011-3013). cyclo(N,5)[Trp(3),Trp(4),Glu(5)]dynorphin A-(1-11)NH(2) showed similar kappa opioid receptor affinity (K(i) = 27 nM) and selectivity (K(i) ratio (kappa/mu/delta) = 1/12/330) to the linear peptide and antagonized dynorphin A-(1-13)NH(2) at kappa opioid receptors. This is the first opioid peptide cyclized through the N-terminus that retains high opioid receptor affinity.