Design and Synthesis of Enantiomerically Pure Decahydroquinoxalines as Potent and Selective κ-Opioid Receptor Agonists with Anti-Inflammatory Activity<i>in Vivo</i>

Soeberdt, Michael; Molenveld, Peter; Storcken, Roy P. M.; Mazery, Renaud Bouzanne des; Sterk, Geert Jan; Autar, Reshma; Bolster, Marjon G.; Wagner, Clemens; Aerts, Sebastianus N. H.; Holst, Frank R. van; Wegert, Anita; Tangherlini, Giovanni; Frehland, Bastian; Schepmann, Dirk; Metze, Dieter; Lotts, Tobias; Knie, Ulrich; Lin, Kun-Yuan; Huang, Tai‐Yu; Lai, Chih-Ching; Ständer, Sonja; Wünsch, Bernhard; Abels, Christoph

doi:10.1021/acs.jmedchem.6b01868

Cited by 18 publications

(26 citation statements)

References 73 publications

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“…• Afamelanotide [43][44][45][46][47][48][49] • Dersimelagon (MT-7117) [50] • KdPT a [51,[54][55][56][57] • WOL074-009, WOL074-019 and WOL074-029 a [58] MC1 and additional effector pathways [85,[87][88][89][90]100] • Asimadoline [58,97,99,100] • Difelikefalin (CR845) [95] • WOL071-007 [92,94] • Compounds 5a [104,105] and 8a [104] • Compounds 3a, 4b, 5a and 5b [103] • Naltrexone [72,73,76,77] • Nalmefene [78][79][80] • Nalbuphine [81][82][83] MOR, KOR, DOR • HU-308 [109,113] • Δ 9 -THC [109,111,112] • CBD [118][119][120]…”

Section: Cutaneous Target System Indication(s)mentioning

confidence: 99%

“…[ 103 ] Peripherally selective substances from this class exhibited dose‐dependent anti‐inflammatory activity in acute and chronic skin inflammation in mice. [ 104 ] One of the substances was shown to modulate epidermal thickness, keratinocyte cell number and apoptosis in situ in human skin organ culture while also influencing mast cells. [ 105 ]…”

Section: Opioid Receptor Modulatorsmentioning

confidence: 99%

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Current and emerging treatments targeting the neuroendocrine system for disorders of the skin and its appendages

Soeberdt

Kilić

Abels

2020

Experimental Dermatology

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The skin as a neuroendocrine organ and the role of neuroendocrine signalling in the development of disorders affecting the skin and its appendages has received increasing attention in the last years. Different neuroendocrine systems have been described in the barrier organ skin, including the thyroid system, the hypothalamicpituitary-adrenal axis, the opioid, the endocannabinoid, the cholinergic, the secosteroidogenic and the serotonergic systems. All of these systems have been implicated in the development of skin diseases, which often have an inflammatory origin. These discoveries have led to an increase in the development of new drugs targeting components of neuroendocrine signalling pathways. Additionally, attempts have been made to repurpose already approved drugs targeting neuroendocrine signalling pathways in other organs for the treatment of skin diseases. Recently published results from preclinical and clinical studies look promising and may offer improved therapies to patients suffering from skin diseases in the near future. In this review, from a pharmaceutical point of view, we focus on recent progress in synthetic drug development of compounds targeting neuroendocrine signalling in the skin and its appendages to treat skin diseases such as atopic dermatitis, psoriasis, acne, alopecia areata and hyperhidrosis.

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Section: Cutaneous Target System Indication(s)mentioning

confidence: 99%

Section: Opioid Receptor Modulatorsmentioning

confidence: 99%

Current and emerging treatments targeting the neuroendocrine system for disorders of the skin and its appendages

Soeberdt

Kilić

Abels

2020

Experimental Dermatology

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“…For the synthesis of hydroxy and fluoro substituted KOR agonists of type 3, the synthetic route previously reported by us to obtain cis,trans-configured perhydroquinoxalines was pursued. [13,33,34] At first, the cyclic sulfuric acid ester amide 10 was prepared in seven steps starting from tetrahydroquinoxaline 9. [13] Nucleophilic ring opening of 10 by (S)-3-hydroxypyrrolidine led to secondary amine 11, which was acylated with 2-(3,4-dichlorophenyl)acetyl chloride to afford the amide 12a.…”

Section: Synthesismentioning

confidence: 99%

“…For the synthesis of hydroxy and fluoro substituted KOR agonists of type 3 , the synthetic route previously reported by us to obtain cis , trans ‐configured perhydroquinoxalines was pursued . At first, the cyclic sulfuric acid ester amide 10 was prepared in seven steps starting from tetrahydroquinoxaline 9 .…”

Section: Synthesismentioning

confidence: 99%

Synthesis and Pharmacological Evaluation of Fluorinated Quinoxaline‐Based κ‐Opioid Receptor (KOR) Agonists Designed for PET Studies

et al. 2020

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k-Opioid receptors (KORs) play a predominant role in pain alleviation, itching skin diseases, depression and neurodegenerative disorders such as multiple sclerosis. Therefore, imaging of KOR by a fluorinated PET tracer was envisaged. Two strategies were followed to introduce a F atom into the very potent class of cis,transconfigured perhydroquinoxalines. Whereas the synthesis of fluoroethyltriazole 2 has already been reported, fluoropyrrolidines 14 (1-[2-(3,4-dichlorophenyl)acetyl]-8-[(R)-3-fluoropyrrolidin-1-yl]-perhydroquinoxalines) were prepared by S N 2 substitution of a cyclic sulfuric acid derivative with hydroxypyrrolidine and subsequent transformation of the OH moiety into a F substituent. Fluoropyrrolidines 14 showed similar low-nanomolar KOR affinity and selectivity to the corresponding pyrrolidines, but the corresponding alcohols were slightly less active. In the cAMP and β-arrestin assay, 14b (proton at the 4-position) exhibited similar KOR agonistic activity as U-50,488. The fluoro derivatives 14b and 14c (CO 2 CH 3 at the 4-position) revealed KOR-mediated anti-inflammatory activity as CD11c and the IFN-γ production were reduced significantly in mouse and human dendritic cells. Compounds 14b and 14-c also displayed antiinflammatory and immunomodulatory activity in mouse and human T cells. The PET tracer [ 18 F]-2 was prepared by 1,3-dipolar cycloaddition. In vivo, [ 18 F]-2 did not label KOR due to very fast elimination kinetics. Nucleophilic substitution of a mesylate precursor provided [ 18 F]-14c. Unfortunately, defluorination of [ 18 F]-14c occurred in vivo, which was analyzed in detail by in vitro studies.

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“…The drugs of interest for topical application have to exhibit particular physico‐chemical characteristics, for example, molecular size (<500 Da), lipophilicity and topological polar surface area, commonly called “small molecules” with “drug‐like properties.” Their drug targets are primarily proteins belonging to enzymes, receptors, transcription factors or ion channels. Activity will be achieved by direct binding and modulation of the target yielding the desired effect .…”

Section: Repurposing Of Neuropharmacological Drugs For Inflammatory Smentioning

confidence: 99%

Can we teach old drugs new tricks?—Repurposing of neuropharmacological drugs for inflammatory skin diseases

Abels

Soeberdt

2019

Experimental Dermatology

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Despite the “hype” for monoclonal antibodies, the so‐called biologics, which added significant value to the therapeutic armamentarium of dermatologists and improved the life of many patients, but may exhibit significant adverse effects, the vast majority of dermatological patients suffering from atopic dermatitis or psoriasis is still treated topically. Thus, there is a huge need for locally applied, locally acting drugs for inflammatory skin diseases with better risk‐benefit profiles compared to topical corticosteroids or calcineurin inhibitors. Drug repositioning is a complex process, but offers advantages, in particular for indications with lower revenues. In this viewpoint, the neuroendocrine system of the skin is described as an attractive drug target because it contributes significantly to neutralizing external noxious agents prior to inducing immune or vascular changes leading to the clinical signs of skin inflammation, for example, itch and erythema. In addition, epidermis and dermis are accessible for topically applied products which may act locally without pharmacodynamically relevant systemic exposure limiting adverse events. Moreover, since numerous drugs have been evaluated for various CNS diseases, some failed and some approved, this resource should be exploited for repurposing as anti‐inflammatory drugs for topical application, for example, cannabidiol, fingolimod or asimadoline. Finally, a screening algorithm is shared which gives direct evidence of links between drug and inflammatory skin diseases.

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Design and Synthesis of Enantiomerically Pure Decahydroquinoxalines as Potent and Selective κ-Opioid Receptor Agonists with Anti-Inflammatory Activityin Vivo

Cited by 18 publications

References 73 publications

Current and emerging treatments targeting the neuroendocrine system for disorders of the skin and its appendages

Current and emerging treatments targeting the neuroendocrine system for disorders of the skin and its appendages

Synthesis and Pharmacological Evaluation of Fluorinated Quinoxaline‐Based κ‐Opioid Receptor (KOR) Agonists Designed for PET Studies

Can we teach old drugs new tricks?—Repurposing of neuropharmacological drugs for inflammatory skin diseases

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