Abstract
The dynorphin (Dyn) A analog arodyn (Ac[Phe1-3,Arg4,d-Ala8]Dyn A-(1–11)NH2) is a κ opioid receptor-selective antagonist, but as a linear peptide it is conformationally flexible and subject to metabolism by proteases. To restrict its conformational flexibility both short- and long-range cyclizations via ring-closing metathesis (RCM) involving residues in both the N-terminal “message” and C-terminal “address” sequences were explored. Cyclization between allyglycine (AllGly) residues in positions 5 and 8 yielded peptides with the highest κ opioid receptor affinity (Ki = 54 and 63 nM) and selectivity for κ over µ receptors (185- and 149-fold) comparable to arodyn (175-fold), with similar results for the peptides with the cis and trans double bond configurations; both isomers exhibited competitive antagonism of κ opioid receptors with potencies similar to arodyn. The minor cis isomer cyclized between AllGly residues in positions 2 and 8 exhibited similar κ receptor affinity to arodyn, but lacked selectivity for κ over µ opioid receptors. These results provide important structure-activity relationship information for cyclization of arodyn that we are using in the design of the next generation of cyclic arodyn analogs. [Figure not available: see fulltext.]
Original language | English (US) |
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Pages (from-to) | 1397-1407 |
Number of pages | 11 |
Journal | Medicinal Chemistry Research |
Volume | 30 |
Issue number | 7 |
DOIs | |
State | Published - Jul 2021 |
Externally published | Yes |
All Science Journal Classification (ASJC) codes
- Pharmacology, Toxicology and Pharmaceutics(all)
- Organic Chemistry