Deletion of Ac‐NMePhe¹ from [NMePhe¹]arodyn under acidic conditions, part 2: Effects of substitutions on pharmacological activity

Abstract

Arodyn (Ac[Phe1,2,3,Arg4,D-Ala8]Dyn A(1-11)-NH2) is an acetylated dynorphin A (Dyn A) analog that is a potent and selective κ opioid receptor antagonist (Bennett et al. J. Med. Chem. 2002, 45, 5617), and its analog [NMePhe1]arodyn shows even higher affinity and selectivity for κ opioid receptors (Bennett et al., J. Pep. Res. 2005, 65, 322). However, the latter compound is prone to deletion of the Ac-NMePhe moiety from the N-terminus of the peptide during acidic cleavage as described in the accompanying paper. Several stable analogs of [NMePhe1]arodyn and [NMePhe1,Trp3]arodyn where the acetyl group was substituted with a heteroatom-containing group were evaluated for their opioid receptor affinity, selectivity, and efficacy. Methoxycarbonyl derivatives exhibited the highest κ opioid receptor affinity among the analogs. Additional CH3OCO[NMePhe1]arodyn analogs where position 3 was substituted with other aromatic or non-aromatic residues were also evaluated for κ receptor affinity, selectivity, and efficacy. [CH3OCO-NMePhe1]arodyn has similar κ opioid receptor affinity as [NMePhe1]arodyn, retains high κ opioid receptor selectivity, and is a potent κ opioid receptor antagonist.

Alanine scan of the opioid peptide dynorphin B amide

“…25 and 26 for reviews). These have included novel cyclization approaches (N‐terminal cyclization and ring‐closing metathesis) and antagonist analogs containing modifications in the N‐terminal “message” sequence, along with some exploration of the SAR of the C‐terminal sequence in these analogs . However, there has been minimal SAR evaluation of Dyn B analogs.…”