Abstract
Arodyn (Ac[Phe 1, 2, 3,Arg,D-Ala]Dy n A(1-11)NH) 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 [NMePhe 1]arodyn shows even higher affinity and selectivity for κ opioid receptors (Bennett et al., J Pept 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 [NMePhe 1]arodyn and [NMePhe 1,Trp 3]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 [CHOCO-NMePhe 1]arodyn analogs where position 3 was substituted with other aromatic or nonaromatic residues were also evaluated for κ receptor affinity, selectivity, and efficacy. [CHOCO-NMePhe 1]arodyn has similar κ opioid receptor affinity as [NMePhe 1]arodyn, retains high κ opioid receptor selectivity, and is a potent κ opioid receptor antagonist.
| Original language | English |
|---|---|
| Pages (from-to) | 103-110 |
| Number of pages | 8 |
| Journal | Biopolymers |
| Volume | 96 |
| Issue number | 1 |
| DOIs | |
| State | Published - 2011 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Biophysics
- Biomaterials
- Organic Chemistry
Cite this
Deletion of Ac-NMePhe(1) from [NMePhe(1) ]arodyn under acidic conditions, part 2 : effects of substitutions on pharmacological activity. / Fang, Wei Jie; Bennett, Marco A.; Murray, Thomas F.; Aldrich, Jane V.
In: Biopolymers, Vol. 96, No. 1, 2011, p. 103-110.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Deletion of Ac-NMePhe(1) from [NMePhe(1) ]arodyn under acidic conditions, part 2
T2 - effects of substitutions on pharmacological activity.
AU - Fang, Wei Jie
AU - Bennett, Marco A.
AU - Murray, Thomas F.
AU - Aldrich, Jane V.
PY - 2011
Y1 - 2011
N2 - Arodyn (Ac[Phe 1, 2, 3,Arg,D-Ala]Dy n A(1-11)NH) 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 [NMePhe 1]arodyn shows even higher affinity and selectivity for κ opioid receptors (Bennett et al., J Pept 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 [NMePhe 1]arodyn and [NMePhe 1,Trp 3]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 [CHOCO-NMePhe 1]arodyn analogs where position 3 was substituted with other aromatic or nonaromatic residues were also evaluated for κ receptor affinity, selectivity, and efficacy. [CHOCO-NMePhe 1]arodyn has similar κ opioid receptor affinity as [NMePhe 1]arodyn, retains high κ opioid receptor selectivity, and is a potent κ opioid receptor antagonist.
AB - Arodyn (Ac[Phe 1, 2, 3,Arg,D-Ala]Dy n A(1-11)NH) 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 [NMePhe 1]arodyn shows even higher affinity and selectivity for κ opioid receptors (Bennett et al., J Pept 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 [NMePhe 1]arodyn and [NMePhe 1,Trp 3]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 [CHOCO-NMePhe 1]arodyn analogs where position 3 was substituted with other aromatic or nonaromatic residues were also evaluated for κ receptor affinity, selectivity, and efficacy. [CHOCO-NMePhe 1]arodyn has similar κ opioid receptor affinity as [NMePhe 1]arodyn, retains high κ opioid receptor selectivity, and is a potent κ opioid receptor antagonist.
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U2 - 10.1002/bip.21495
DO - 10.1002/bip.21495
M3 - Article
VL - 96
SP - 103
EP - 110
JO - Biopolymers
JF - Biopolymers
SN - 0006-3525
IS - 1
ER -