Deletion of Ac‐NMePhe1 from [NMePhe1]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. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 96: 103–110, 2011.

[1]  J. V. Aldrich,et al.  Reinstatement of cocaine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodyn. , 2007, European journal of pharmacology.

[2]  M. Aceto,et al.  Effects of JDTic, a selective kappa-opioid receptor antagonist, on the development and expression of physical dependence on morphine using a rat continuous-infusion model. , 2005, European journal of pharmacology.

[3]  James L. Howard,et al.  Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats , 2005, Psychopharmacology.

[4]  T. F. Murray,et al.  Structure-activity relationships of arodyn, a novel acetylated kappa opioid receptor antagonist. , 2005, The journal of peptide research : official journal of the American Peptide Society.

[5]  James L. Howard,et al.  Pharmacological properties of JDTic: a novel κ-opioid receptor antagonist , 2004 .

[6]  P. Schiller,et al.  Structure-activity relationships of dynorphin a analogues modified in the address sequence. , 2003, Journal of medicinal chemistry.

[7]  Philip S. Portoghese,et al.  Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in the Forced Swim Test in Rats , 2003, Journal of Pharmacology and Experimental Therapeutics.

[8]  B. Vig,et al.  A novel N-terminal cyclic dynorphin A analogue cyclo(N,5)[Trp(3),Trp(4),Glu(5)] dynorphin A-(1-11)NH(2) that lacks the basic N-terminus. , 2003, Journal of medicinal chemistry.

[9]  T. F. Murray,et al.  Identification of arodyn, a novel acetylated dynorphin A-(1-11) analogue, as a kappa opioid receptor antagonist. , 2002, Journal of medicinal chemistry.

[10]  N. Mello,et al.  Kappa opioid antagonist effects of the novel kappa antagonist 5′-guanidinonaltrindole (GNTI) in an assay of schedule-controlled behavior in rhesus monkeys , 2002, Psychopharmacology.

[11]  P. Schiller,et al.  [2',6'-Dimethyltyrosine]dynorphin A(1-11)-NH2 analogues lacking an N-terminal amino group: potent and selective kappa opioid antagonists. , 2001, Journal of medicinal chemistry.

[12]  J. Zeldis.  Drug development: Molecular targets for GI disease , 2001 .

[13]  F I Carroll,et al.  Identification of the first trans-(3R,4R)- dimethyl-4-(3-hydroxyphenyl)piperidine derivative to possess highly potent and selective opioid kappa receptor antagonist activity. , 2001, Journal of medicinal chemistry.

[14]  P. Schiller,et al.  [Pro(3)]Dyn A(1-11)-NH(2): a dynorphin analogue with high selectivity for the kappa opioid receptor. , 2000, Journal of medicinal chemistry.

[15]  R. M. Jones,et al.  Potent and selective indolomorphinan antagonists of the kappa-opioid receptor. , 2000, Journal of medicinal chemistry.

[16]  B. H. Hill,et al.  An open-label study of a functional opioid κ antagonist in the treatment of opioid dependence , 2000 .

[17]  T. F. Murray,et al.  A novel acetylated analogue of dynorphin A-(1-11) amide as a κ-opioid receptor antagonist , 1999 .

[18]  C. Belzung,et al.  The role of subtypes of the opioid receptor in the anxiolytic action of chlordiazepoxide , 1998, Neuropharmacology.

[19]  T. F. Murray,et al.  N-alkylated derivatives of [D-Pro10]dynorphin A-(1-11) are high affinity partial agonists at the cloned rat kappa-opioid receptor. , 1997, European journal of pharmacology.

[20]  M. Wolff,et al.  BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY , 1996 .

[21]  M. Tsuda,et al.  Involvement of the opioid system in the anxiolytic effect of diazepam in mice. , 1996, European journal of pharmacology.

[22]  T. F. Murray,et al.  Synthesis and opioid activity of conformationally constrained dynorphin A analogues. 1. Conformational constraint in the "message" sequence. , 1995, Journal of medicinal chemistry.

[23]  P. Delafontaine,et al.  Regulation of Vascular Smooth Muscle Cell Insulin-like Growth Factor I Receptors by Phosphorothioate Oligonucleotides. EFFECTS ON CELL GROWTH AND EVIDENCE THAT SENSE TARGETING AT THE ATG SITE INCREASES RECEPTOR EXPRESSION (*) , 1995, The Journal of Biological Chemistry.

[24]  Robert C. Thompson,et al.  A Chimeric Study of the Molecular Basis of Affinity and Selectivity of the κ and the δ Opioid Receptors. , 1995, The Journal of Biological Chemistry.

[25]  C. Chen,et al.  Differential binding domains of peptide and non-peptide ligands in the cloned rat kappa opioid receptor. , 1994, The Journal of biological chemistry.

[26]  G. Uhl,et al.  Human kappa opiate receptor second extracellular loop elevates dynorphin's affinity for human mu/kappa chimeras. , 1994, The Journal of biological chemistry.

[27]  P. Rubin,et al.  The cardiovascular and central nervous system effects in the human of U-62066E , 1994, European Journal of Clinical Pharmacology.

[28]  N. Solé,et al.  Optimization of solid-phase synthesis of [Ala8]-dynorphin A , 1992 .

[29]  H. Yamamura,et al.  Extremely long-lasting antagonistic actions of nor-binaltorphimine (nor-BNI) in the mouse tail-flick test. , 1992, The Journal of pharmacology and experimental therapeutics.

[30]  A. Lipkowski,et al.  Bimorphinans as highly selective, potent kappa opioid receptor antagonists. , 1987, Journal of medicinal chemistry.

[31]  H. Emrich,et al.  Psychotomimesis mediated by kappa opiate receptors , 1986, Science.

[32]  A Goldstein,et al.  Specific receptor for the opioid peptide dynorphin: structure--activity relationships. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Y. Cheng,et al.  Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. , 1973, Biochemical pharmacology.

[34]  P. Rivière,et al.  Opioid Receptors: Targets for New Gastrointestinal Drug Development , 2000 .