Illudalic acid as a potential LAR inhibitor: Synthesis, SAR, and preliminary studies on the mechanism of action

Ling, Qing; Huang, Yue; Zhou, Yuwei; Cai, Zheng-Liang; Xiong, Bing; Zhang, Yahui; Ma, Li; Wang, Xin; Li, Xin; Li, Jia; Shen, Jingkang

doi:10.1016/j.bmc.2008.06.014

Cited by 23 publications

(53 citation statements)

References 70 publications

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“…dosing greater than 20 mg/kg is thus problematic. The slow in vitro onset of PTPRD phosphatase inhibition is compatible with the pseudoirreversible mechanism of action that has been postulated for illudalic acid analog interactions with PTPRF, perhaps providing another limitation (21). We have documented levels of 7-BIA/metabolites in brains of mice killed at times when 7-BIA administration provides behavioral effects, but we have only limited information about 7-BIA's cellular permeability.…”

Section: Discussionmentioning

confidence: 56%

“…PTPRD is a member of a "DSF" subfamily of receptor type protein tyrosine phosphatases that also includes PTPRS and PTPRF. Natural product library screening has identified illudalic acid ligands that display micromolar IC 50 values (21,22) in inhibiting PTPRF's phosphatase. Interest in the phosphatase "business end" of PTPRD as a drug target is increased by nonconservative amino acid differences between PTPRF, PTPRD, and PTPRS phosphatase domains (23) that could allow specificity for PTPRD phosphatase inhibitors.…”

Section: Significancementioning

confidence: 99%

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Cocaine reward is reduced by decreased expression of receptor-type protein tyrosine phosphatase D (PTPRD) and by a novel PTPRD antagonist

Uhl

Martínez

Paik

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Receptor-type protein tyrosine phosphatase D (PTPRD) is a neuronal cell-adhesion molecule/synaptic specifier that has been implicated in addiction vulnerability and stimulant reward by human genomewide association and mouse cocaine-conditioned place-preference data. However, there have been no reports of effects of reduced expression on cocaine self-administration. There have been no reports of PTPRD targeting by any small molecule. There are no data about behavioral effects of any PTPRD ligand. We now report (i) robust effects of heterozygous PTPRD KO on cocaine self-administration (These data substantially extend prior conditioned place-preference data and add to the rationale for PTPRD as a target for addiction therapeutics.); (ii) identification of 7-butoxy illudalic acid analog (7-BIA) as a small molecule that targets PTPRD and inhibits its phosphatase with some specificity; (iii) lack of toxicity when 7-BIA is administered to mice acutely or with repeated dosing; (iv) reduced cocaine-conditioned place preference when 7-BIA is administered before conditioning sessions; and (v) reductions in well-established cocaine self-administration when 7-BIA is administered before a session (in WT, not PTPRD heterozygous KOs). These results add to support for PTPRD as a target for medications to combat cocaine use disorders. 7-BIA provides a lead compound for addiction therapeutics.

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Section: Discussionmentioning

confidence: 56%

Section: Significancementioning

confidence: 99%

Cocaine reward is reduced by decreased expression of receptor-type protein tyrosine phosphatase D (PTPRD) and by a novel PTPRD antagonist

Uhl

Martínez

Paik

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…The synthesis of alcohol 8 was performed as described by Ling et al . The Mitsunobu reaction is one of the most convenient methods for the conversion of secondary alcohols to their azide derivatives .…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Carbonic Anhydrase Inhibitory Effects of Novel Sulfamides Derived from 1‐Aminoindanes and Anilines

Akbaba

Bastem

Topal

et al. 2014

Archiv der Pharmazie

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Three 1-aminoindanes, four anilines and BnOH or t-BuOH were reacted with chlorosulfonyl isocyanate to give sulfamoyl carbamates. Pd-C catalysed hydrogenolysis reactions of carbamates or deprotection of the Boc group of the carbamates with CF3 CO2 H afforded seven novel sulfamides. Human carbonic anhydrase (hCA) isoenzymes I and II (hCA I and hCA II) were purified from fresh human blood erythrocytes with one-step affinity chromatography on Sepharose 4B-tyrosine-sulfanilamide. The inhibitory properties of the novel sulfamides on both isoenzymes were determined using the esterase activity with 4-nitrophenyl acetate (NPA) as substrate. The tested novel sulfamides derived from 1-aminoindanes and anilines effectively inhibited hCA I and II competitively in the nanomolar range. Among these compounds, the novel sulfamide derivative 17 showed the most potent inhibitory effect against hCA I (Ki : 153.88 nM), while sulfamide derivative 26 showed the highest inhibitory potential against hCA II (Ki : 117.80 nM).

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“…We have focused on inhibitors of PTPRD's phosphatase domain as a novel approach to “drugging” PTPRD for several reasons Natural product library screening identified ligands that inhibit PTPRF's phosphatase activity. Illudalic acid displays micromolar K i in inhibiting PTPRF's phosphatase. Illudalic acid analogs thus provided exciting clues to possible PTPRD ligands.…”

Section: Discovery and Effects Of The Initial Ptprd Ligandmentioning

confidence: 99%

PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes

Uhl

Martínez

2019

Annals of the New York Academy of Sciences

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Receptor‐type protein tyrosine phosphatase, receptor type D (PTPRD) has likely roles as a neuronal cell adhesion molecule and synaptic specifier. Interest in its neurobiology and genomics has been stimulated by results from human genetics and mouse models for phenotypes related to addiction, restless leg syndrome, neurofibrillary pathology in Alzheimer's disease, cognitive impairment/intellectual disability, mood lability, and obsessive‐compulsive disorder. We review PTPRD's discovery, gene family, candidate homomeric and heteromeric binding partners, phosphatase activities, brain distribution, human genetic associations with nervous system phenotypes, and mouse model data relevant to these phenotypes. We discuss the recently reported discovery of the first small molecule inhibitor of PTPRD phosphatase, the identification of its addiction‐related effects, and the implications of these findings for the PTPRD‐associated brain phenotypes. In assembling PTPRD neurobiology, human genetics, and mouse genetic and pharmacological datasets, we provide a compelling picture of the roles played by PTPRD, its variation, and its potential as a target for novel therapeutics.

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Illudalic acid as a potential LAR inhibitor: Synthesis, SAR, and preliminary studies on the mechanism of action

Cited by 23 publications

References 70 publications

Cocaine reward is reduced by decreased expression of receptor-type protein tyrosine phosphatase D (PTPRD) and by a novel PTPRD antagonist

Cocaine reward is reduced by decreased expression of receptor-type protein tyrosine phosphatase D (PTPRD) and by a novel PTPRD antagonist

Synthesis and Carbonic Anhydrase Inhibitory Effects of Novel Sulfamides Derived from 1‐Aminoindanes and Anilines

PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes

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