Deletion of Ac-NMePhe(1) from [NMePhe(1) ]arodyn under acidic conditions, part 2: effects of substitutions on pharmacological activity.
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 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 [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 nonaromatic 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.
Fang
Wei-Jie
WJ
Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045, USA.
Bennett
Marco A
MA
Murray
Thomas F
TF
Aldrich
Jane V
JV
D000143:Acids / Q000737:chemistry; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D004399:Dynorphins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008745:Methylation; D008956:Models, Chemical; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000737:chemistry / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism
D000143:Acids; D000596:Amino Acids; D010455:Peptides; D017473:Receptors, Opioid, kappa; C470200:arodyn; D014443:Tyrosine; C028544:cyclohexylalanine; D010649:Phenylalanine; D004399:Dynorphins; D014364:Tryptophan