The interaction of N alpha-alkylenkephalins with opiate receptors. Tissue-dependent shifts in the opiate activity of methionine-enkephalin following N alpha-alkylation.

Summers, Michael C.; R, Hayes

doi:10.1016/s0021-9258(19)69350-6

Cited by 18 publications

(13 citation statements)

References 44 publications

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“…The bulkier N -phenylacetyl (KK-81), N -tolylacetyl (KK-82), and N -cyclohexanoyl (KK-112) also showed reduced binding affinity compared to KK-102. Our results agree with the previous report and suggest that there is an optimal size of the N -terminal modification to preserve binding affinity with DOR [ 23 ].…”

Section: Resultssupporting

confidence: 93%

“…Additionally, it has been shown that adding amino acids to the N -terminus of Leu-ENK does not result in loss of activity [ 30 ]. Summers et al investigated the binding affinity of N -alkylated Met-ENK for mouse DOR and found that N -hexyl derivatives displayed the strongest binding and that analogs with a shorter or longer alkyl chain showed decreased binding [ 23 ]. Similarly, among the Leu-ENK analogs investigated in this study, N -pivaloyl-Leu-ENK (KK-102) exhibited the strongest DOR binding (70% relative to Leu-ENK), while analogs with a smaller ( N -acetyl: KK-14) or larger N -alkylated modification ( N -pentenoyl: KK-105; N -hexanoyl: KK-93; N -octanoyl: KK108) displayed decreased DOR binding (30–60% relative to Leu-ENK).…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies mainly employed bulky terminal attachments such as fatty acids [ 21 ] and fluorenylmethyloxycarbonyl-based moieties [ 22 ]. Short N -alkyl modifications have been studied to analyze their impact on the receptor binding in vitro but were not investigated in vivo [ 23 ]. Moreover, in those prior studies, additional backbone modifications with d-amino acids [ 23 , 24 , 25 ], or a different linker between amino acids, such as squaric acid [ 12 ], cyclopropane [ 13 ], alkenes [ 14 ], triazoles [ 15 ], and thioethers [ 16 ], were also performed to enhance the proteolytic stability.…”

Section: Introductionmentioning

confidence: 99%

“…Short N -alkyl modifications have been studied to analyze their impact on the receptor binding in vitro but were not investigated in vivo [ 23 ]. Moreover, in those prior studies, additional backbone modifications with d-amino acids [ 23 , 24 , 25 ], or a different linker between amino acids, such as squaric acid [ 12 ], cyclopropane [ 13 ], alkenes [ 14 ], triazoles [ 15 ], and thioethers [ 16 ], were also performed to enhance the proteolytic stability. The chemical structures of some of these previously reported ENK derivatives are summarized in Figure S1 (see Supporting Information) .…”

Section: Introductionmentioning

confidence: 99%

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An Effective and Safe Enkephalin Analog for Antinociception

et al. 2021

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Opioids account for 69,000 overdose deaths per annum worldwide and cause serious side effects. Safer analgesics are urgently needed. The endogenous opioid peptide Leu-Enkephalin (Leu-ENK) is ineffective when introduced peripherally due to poor stability and limited membrane permeability. We developed a focused library of Leu-ENK analogs containing small hydrophobic modifications. N-pivaloyl analog KK-103 showed the highest binding affinity to the delta opioid receptor (68% relative to Leu-ENK) and an extended plasma half-life of 37 h. In the murine hot-plate model, subcutaneous KK-103 showed 10-fold improved anticonception (142%MPE·h) compared to Leu-ENK (14%MPE·h). In the formalin model, KK-103 reduced the licking and biting time to ~50% relative to the vehicle group. KK-103 was shown to act through the opioid receptors in the central nervous system. In contrast to morphine, KK-103 was longer-lasting and did not induce breathing depression, physical dependence, and tolerance, showing potential as a safe and effective analgesic.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An Effective and Safe Enkephalin Analog for Antinociception

et al. 2021

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“…10 It is reasonable to suppose that glycation of the N-terminal amino group of the tyrosine residue will affect the biological activity of Leu-enkephalin since it was shown that after N-alkylation of enkephalins, depending on substitution pattern, activity may be enhanced, reduced, eliminated or even reversed to give antagonists. 11 Although there have been many contributions in the last few years which demonstrate that nonenzymatic glycation leads to functional changes in the affectedproteins, 1-4 little is known of how the attached carbohydrate molecule influences the conformational properties of the N-alkylated protein.…”

Section: Introductionmentioning

confidence: 99%

CD and FTIR spectroscopic studies of Amadori compounds related to the opioid peptides

Horvat

Jakas

Vass

et al. 1997

J. Chem. Soc., Perkin Trans. 2

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Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents

2002

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Reductive amination is an important tool for synthetic organic chemists in the construction of carbon‐nitrogen bonds. This reaction, also termed reductive alkylation, involves condensation of an aldehyde or ketone with an amine in the presence of a reducing agent. A wide variety of substrates can be used including aliphatic and aromatic aldehydes and ketones, and even benzophenones. A range of amines from ammonia to aromatic amines, including those with electron‐withdrawing substituents, can be employed. For particularly sluggish reactions, such as those involving weakly electrophilic carbonyl groups, poorly nucleophilic amines, or sterically congested reactive centers, additives such as molecular sieves or Lewis acids are often useful. This chapter focuses on those conditions in which the carbonyl component, amine, and reducing reagent react in the same vessel. This review is restricted to reductive aminations using borohydride and borane reducing agents. This chapter concentrates on reductive amination chemistry mediated by borohydride and other boron‐containing reducing agents from 1971, the year when sodium cyanoborohydride was introduced, through the middle of 1999. In addition to reductive aminations of aldehyde and ketone substrates, reactions of related structures including acetals, aminals, ketals, carboxylic acids, nitriles, and dicarbonyls that form a nitrogen‐containing ring are reviewed. Intramolecular processes in which the substrate contains both the carbonyl and amine moieties are described. The intramolecular variant is a useful method for preparing cyclic amines. All of the various boron‐containing hydride sources in reductive aminations, including labeled metal hydrides, are reviewed. Instances of reductive aminations that failed are described. Applications of this method to a solid support in parallel synthesis in combinatorial chemistry as well as reductive aminations that proceed in tandem with a second reaction such as reductive lactamizations are discussed.

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The interaction of N alpha-alkylenkephalins with opiate receptors. Tissue-dependent shifts in the opiate activity of methionine-enkephalin following N alpha-alkylation.

Cited by 18 publications

References 44 publications

An Effective and Safe Enkephalin Analog for Antinociception

An Effective and Safe Enkephalin Analog for Antinociception

CD and FTIR spectroscopic studies of Amadori compounds related to the opioid peptides

Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents

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