Joshi, Anand AnantMurray, Thomas F.Aldrich, Jane V.2018-09-142018-09-142017-05-02Anand A. Joshi, Thomas F. Murray, Jane V. Aldrich Biopolymers. 2017 Sep; 108(5): 10.1002/bip.23026. doi: 10.1002/bip.23026https://hdl.handle.net/1808/26726To date structure-activity relationship (SAR) studies of the dynorphins (Dyn), endogenous peptides for kappa opioid receptors (KOR), have focused almost exclusively on Dyn A with minimal studies on Dyn B. While both Dyn A and Dyn B have identical N-terminal sequences, their C-terminal sequences differ which could result in differences in pharmacological activity. We performed an alanine scan of the non-glycine residues up through residue 11 of Dyn B amide to explore the role of these side chains in the activity of Dyn B. The analogs were synthesized by fluorenylmethyloxycarbonyl (Fmoc)-based solid phase peptide synthesis and evaluated for their opioid receptor affinities and opioid potency and efficacy at KOR. Similar to Dyn A the N-terminal Tyr1 and Phe4 residues of Dyn B amide are critical for opioid receptor affinity and KOR agonist potency. The basic residues Arg6 and Arg7 contribute to the KOR affinity and agonist potency of Dyn B amide, while Lys10 contributes to the opioid receptor affinity, but not KOR agonist potency, of this peptide. Comparison to the Ala analogs of Dyn A(1-13) suggests that the basic residues in the C-terminus of both peptides contribute to KOR binding, but differences in their relative positions may contribute to the different pharmacological profiles of Dyn A and Dyn B. The other unique C-terminal residues in Dyn B amide also appear to influence the relative affinity of this peptide for KOR. This SAR information may be applied in the design of new Dyn B analogs that could be useful pharmacological toolsDynorphin BAlanine scanKappa opioid receptorStructure-activity relationshipsC-terminal basic residuesArticle10.1002/bip.23026PMC6003702openAccess