N-Alkylated derivatives of [d-Pro10]dynorphin A-(1-11) are high affinity partial agonists at the cloned rat κ-opioid receptor

Soderstrom, Ken; Choi, Heekyung; Berman, Frederick W.; Aldrich, Jane V.; Murray, Thomas F.

doi:10.1016/s0014-2999(97)81948-6

Cited by 32 publications

(52 citation statements)

References 18 publications

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“…However, the very low affinity of the linear peptide 12 suggests that the N-terminal alkyl group may be a major reason for the low affinity of the cyclic peptides. The reduced affinity of the N-acetamide Dyn A analogs compared to previously reported N-alkyl analogs 38,52 suggests that the electronic effects of the acetamide group at the N-terminus may be responsible for the reduced affinity. Alternative linkers between the N-terminus and a side chain may be better tolerated by opioid receptors and will be examined in the future.…”

Section: Discussionmentioning

confidence: 70%

Synthesis of novel basic head‐to‐side‐chain cyclic dynorphin A analogs: Strategies and side reactions

2003

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Novel N-terminus-to-side-chain cyclic analogs of the opioid peptide dynorphin (Dyn) A-(1-11)NH(2) were prepared that retain the basicity of the N-terminal amine and restrict the backbone conformation around the important Tyr(1) residue. Cyclic peptides were synthesized in which the N-terminal amine and the N(epsilon)-amine of a Lys at position 3 or 5 were attached to the alpha-carbon and carbonyl of an acetyl group, respectively. Several synthetic strategies were explored with detailed analysis of the side reactions in order to obtain the desired cyclic peptides. One of the side reactions observed involved premature loss of the N-terminal 9-fluorenylmethoxycarbonyl (Fmoc) group during the neutralization step following deprotection of the Mtt (4-methyltrityl) protecting group from the side chain of Lys. The successful strategy involved the synthesis of the linear peptide up through Gly(2) and functionalization through the N(epsilon)-amine of Lys. A linear N-terminal alkylated analog was prepared by alkylation of the peptide on the resin with an equimolar amount of bromoacetamide, followed by treatment of the peptide with Fmoc-OSu prior to cleavage from the resin to facilitate separation by reversed phase high performance liquid chromatography of unreacted peptide from the desired alkylated product. The novel N-terminal cyclic Dyn A analogs and the linear analog were evaluated for their opioid receptor affinities. These peptides exhibited large losses in affinity for opioid receptors; the low affinity of the linear N-terminal alkylated peptide suggested that the alpha-acetamide group on the N-terminal amine resulted in unfavorable interactions with opioid receptors.

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Section: Discussionmentioning

confidence: 70%

Synthesis of novel basic head‐to‐side‐chain cyclic dynorphin A analogs: Strategies and side reactions

2003

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“…These arodyn analogs were evaluated for their efficacy at 10 μM to inhibit adenylyl cyclase (AC) using cloned rat κ opioid receptors stably expressed on CHO cells 33. The analogs exhibited negligible or low efficacy in this assay (≥74% of the control (≤26% inhibition) compared to Dyn A-(1-13)NH 2 , Table 2), similar to arodyn.…”

Section: Resultsmentioning

confidence: 94%

“…The AC assay was performed using cloned rat κ opioid receptors stably expressed on CHO cells as previously described 33. The inhibition of cAMP production was determined for each peptide at 10 μM compared untreated controls and the reference agonist Dyn A-(1-13)NH 2 ; the results presented (Tables 2 and 3) are the mean ± SEM from at least three separate assays.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2011

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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.

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“…N-monoalkylated and N, N-dialkylated Tyr derivatives of [D-Pro 10 ]DynA(1-11) 68 with benzyl (Bz) and cyclopropylmethyl (Cpm) substituents 69-72 were synthesized to explore the structure-activity relationships for antagonist vs. agonist activity at κ-opioid receptor [80]. In general, the N-monoalkylated derivatives exhibited much higher affinity and greatly enhanced selectivity compared to the N,N-dialkylated analogs.…”

Section: Methylation Of the Aromatic Rings Of Tyrosine And Phenylalaninementioning

confidence: 99%

Conformationally Restricted Peptides as Tools in Opioid Receptor Studies

Janecka¹,

Kruszyński

2005

CMC

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The discovery of endogenous opioid peptides with their limited receptor selectivity more than two decades ago implicated their involvement in analgesia and initiated efforts to understand the molecular mechanisms underlying their action. Opioid peptides mediate their physiological and pharmacological effects through three major opioid receptor types (mu, delta, kappa), but the role of each of these receptors is not easy to distinguish. There has therefore, been an increasing need for potent and selective agonists and antagonists in this area. The incorporation of conformational constraints into analogs of biologically active peptides is a well-known approach for enhancing receptor selectivity and modulating efficacy. Conformational restriction has proven a valuable means for assessing disparities between the peptide binding characteristics at each of the opioid receptor types, since peptide analogs designed with appropriate conformational constraints possess the ability to adopt the conformation required for interaction at one receptor type but not another. In efforts to obtain better conformational integrity various conformationally restricted analogs of endogenous opioid peptides have been developed. In this paper we review the development of opioid analogs whose conformation was restricted either globally through different types of cyclization (such as amide bond formation, disulfide and monosulfide bridges, carbonyl and amine bridges) or locally, through incorporation of side-chain conformational constraints at a specific amino acid residue by synthesizing cyclic amino acids or constraining torsion angles by suitable substitutions. These two approaches have led to the development of potent and very selective agonists and antagonists at all three opioid receptor types.

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N-Alkylated derivatives of [d-Pro10]dynorphin A-(1-11) are high affinity partial agonists at the cloned rat κ-opioid receptor

Cited by 32 publications

References 18 publications

Synthesis of novel basic head‐to‐side‐chain cyclic dynorphin A analogs: Strategies and side reactions

Synthesis of novel basic head‐to‐side‐chain cyclic dynorphin A analogs: Strategies and side reactions

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

Conformationally Restricted Peptides as Tools in Opioid Receptor Studies

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N-Alkylated derivatives of [d-Pro10]dynorphin A-(1-11) are high affinity partial agonists at the cloned rat κ-opioid receptor

Cited by 32 publications

References 18 publications

Synthesis of novel basic head‐to‐side‐chain cyclic dynorphin A analogs: Strategies and side reactions

Synthesis of novel basic head‐to‐side‐chain cyclic dynorphin A analogs: Strategies and side reactions

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

Conformationally Restricted Peptides as Tools in Opioid Receptor Studies

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