Publications by authors named "Mark E McDonnell"

18 Publications

  • Page 1 of 1

The discovery of azetidine-piperazine di-amides as potent, selective and reversible monoacylglycerol lipase (MAGL) inhibitors.

Bioorg Med Chem Lett 2020 07 7;30(14):127243. Epub 2020 May 7.

Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA.

Monoacylglycerol lipase (MAGL) is the enzyme that is primarily responsible for hydrolyzing the endocannabinoid 2-arachidononylglycerol (2-AG) to arachidonic acid (AA). It has emerged in recent years as a potential drug target for a number of diseases. Herein, we report the discovery of compound 6g from a series of azetidine-piperazine di-amide compounds as a potent, selective, and reversible inhibitor of MAGL. Oral administration of compound 6g increased 2-AG levels in rat brain and produced full efficacy in the rat complete Freund's adjuvant (CFA) model of inflammatory pain.
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http://dx.doi.org/10.1016/j.bmcl.2020.127243DOI Listing
July 2020

Non-NAD-like PARP-1 inhibitors in prostate cancer treatment.

Biochem Pharmacol 2019 09 15;167:149-162. Epub 2019 Mar 15.

University of North Dakota, Grand Forks, ND, United States. Electronic address:

In our previous studies of the molecular mechanisms of poly(ADP-ribose) polymerase 1 (PARP-1)-mediated transcriptional regulation we identified a novel class of PARP-1 inhibitors targeting the histone-dependent route of PARP-1 activation. Because histone-dependent activation is unique to PARP-1, non-NAD-like PARP-1 inhibitors have the potential to bypass the off-target effects of classical NAD-dependent PARP-1 inhibitors, such as olaparib, veliparib, and rucaparib. Furthermore, our recently published studies demonstrate that, compared to NAD-like PARP-1 inhibitors that are used clinically, the non-NAD-like PARP-1 inhibitor 5F02 exhibited superior antitumor activity in cell and animal models of human prostate cancer (PC). In this study, we further evaluated the antitumor activity of 5F02 and several of its novel analogues against PC cells. In contrast to NAD-like PARP-1 inhibitors, non-NAD-like PARP-1 inhibitors demonstrated efficacy against androgen-dependent and -independent routes of androgen receptor signaling activation. Our experiments reveal that methylation of the quaternary ammonium salt and the presence of esters were critical for the antitumor activity of 5F02 against PC cells. In addition, we examined the role of a related regulatory protein of PARP-1, called Poly(ADP-ribose) glycohydrolase (PARG), in prostate carcinogenesis. Our study reveals that PARG expression is severely disrupted in PC cells, which is associated with decreased integrity and localization of Cajal bodies (CB). Overall, the results of our study strengthen the justification for using non-NAD-like PARP-1 inhibitors as a novel therapeutic strategy for the treatment of advanced prostate cancer.
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http://dx.doi.org/10.1016/j.bcp.2019.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702078PMC
September 2019

Structure-based design of small-molecule inhibitors of EBNA1 DNA binding blocks Epstein-Barr virus latent infection and tumor growth.

Sci Transl Med 2019 03;11(482)

The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.

Epstein-Barr virus (EBV) is a DNA tumor virus responsible for 1 to 2% of human cancers including subtypes of Burkitt's lymphoma, Hodgkin's lymphoma, gastric carcinoma, and nasopharyngeal carcinoma (NPC). Persistent latent infection drives EBV-associated tumorigenesis. Epstein-Barr nuclear antigen 1 (EBNA1) is the only viral protein consistently expressed in all EBV-associated tumors and is therefore an attractive target for therapeutic intervention. It is a multifunctional DNA binding protein critical for viral replication, genome maintenance, viral gene expression, and host cell survival. Using a fragment-based approach and x-ray crystallography, we identify a 2,3-disubstituted benzoic acid series that selectively inhibits the DNA binding activity of EBNA1. We characterize these inhibitors biochemically and in cell-based assays, including chromatin immunoprecipitation and DNA replication assays. In addition, we demonstrate the potency of EBNA1 inhibitors to suppress tumor growth in several EBV-dependent xenograft models, including patient-derived xenografts for NPC. These inhibitors selectively block EBV gene transcription and alter the cellular transforming growth factor-β (TGF-β) signaling pathway in NPC tumor xenografts. These EBNA1-specific inhibitors show favorable pharmacological properties and have the potential to be further developed for the treatment of EBV-associated malignancies.
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http://dx.doi.org/10.1126/scitranslmed.aau5612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936217PMC
March 2019

Cypin: A novel target for traumatic brain injury.

Neurobiol Dis 2018 11 19;119:13-25. Epub 2018 Jul 19.

Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Piscataway, NJ 08854-8082, USA. Electronic address:

Cytosolic PSD-95 interactor (cypin), the primary guanine deaminase in the brain, plays key roles in shaping neuronal circuits and regulating neuronal survival. Despite this pervasive role in neuronal function, the ability for cypin activity to affect recovery from acute brain injury is unknown. A key barrier in identifying the role of cypin in neurological recovery is the absence of pharmacological tools to manipulate cypin activity in vivo. Here, we use a small molecule screen to identify two activators and one inhibitor of cypin's guanine deaminase activity. The primary screen identified compounds that change the initial rate of guanine deamination using a colorimetric assay, and secondary screens included the ability of the compounds to protect neurons from NMDA-induced injury and NMDA-induced decreases in frequency and amplitude of miniature excitatory postsynaptic currents. Hippocampal neurons pretreated with activators preserved electrophysiological function and survival after NMDA-induced injury in vitro, while pretreatment with the inhibitor did not. The effects of the activators were abolished when cypin was knocked down. Administering either cypin activator directly into the brain one hour after traumatic brain injury significantly reduced fear conditioning deficits 5 days after injury, while delivering the cypin inhibitor did not improve outcome after TBI. Together, these data demonstrate that cypin activation is a novel approach for improving outcome after TBI and may provide a new pathway for reducing the deficits associated with TBI in patients.
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http://dx.doi.org/10.1016/j.nbd.2018.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214165PMC
November 2018

Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability.

ACS Med Chem Lett 2016 Apr 10;7(4):424-8. Epub 2016 Feb 10.

KannaLife Sciences , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.

Cannabidiol is the nonpsychoactive natural component of C. sativa that has been shown to be neuroprotective in multiple animal models. Our interest is to advance a therapeutic candidate for the orphan indication hepatic encephalopathy (HE). HE is a serious neurological disorder that occurs in patients with cirrhosis or liver failure. Although cannabidiol is effective in models of HE, it has limitations in terms of safety and oral bioavailability. Herein, we describe a series of side chain modified resorcinols that were designed for greater hydrophilicity and "drug likeness", while varying hydrogen bond donors, acceptors, architecture, basicity, neutrality, acidity, and polar surface area within the pendent group. Our primary screen evaluated the ability of the test agents to prevent damage to hippocampal neurons induced by ammonium acetate and ethanol at clinically relevant concentrations. Notably, KLS-13019 was 50-fold more potent and >400-fold safer than cannabidiol and exhibited an in vitro profile consistent with improved oral bioavailability.
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http://dx.doi.org/10.1021/acsmedchemlett.6b00009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834656PMC
April 2016

Intramolecular Rearrangement of α-Amino Acid Amide Derivatives of 2-Aminobenzothiazoles.

Tetrahedron Lett 2014 Jul;55(30):4193-4195

Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Rd., Doylestown, PA 18902.

We have found that α-amino acid amide derivatives of 2-aminobenzothiazoles undergo a time-dependent, thermal rearrangement in which the amine group attacks the 2-position carbon of the thiazole ring to form a 5,5-spiro ring system. This is followed by sulfur leaving and air oxidation to the corresponding symmetrical disulfide. The isolated yields of such products are quite high (>70%) if there is conformational bias to further promote the intramolecular reaction such as for the 2-aminobenzothiazole amides derived from proline or 4-aminopiperidine-4-carboxylic acid. This rearrangement has not been described previously for α-amino acid amide derivatives of 2-aminobenzothiazoles. However, a related reaction involving 2-semicarbazido benzothiazoles has been recently reported.
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http://dx.doi.org/10.1016/j.tetlet.2014.05.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090782PMC
July 2014

Anilino-monoindolylmaleimides as potent and selective JAK3 inhibitors.

Bioorg Med Chem Lett 2014 Feb 9;24(4):1116-21. Epub 2014 Jan 9.

Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Road, Doylestown, PA 18902, United States.

We designed a series of anilino-indoylmaleimides based on structural elements from literature JAK3 inhibitors 3 and 4, and our lead 5. These new compounds were tested as inhibitors of JAKs 1, 2 and 3 and TYK2 for therapeutic intervention in rheumatoid arthritis (RA). Our requirements, based on current scientific rationale for optimum efficacy against RA with reduced side effects, was for potent, mixed JAK1 and 3 inhibition, and selectivity over JAK2. Our efforts yielded a potent JAK3 inhibitor 11d and its eutomer 11e. These compounds were highly selective for inhibition of JAK3 over JAK2 and TYK. The compounds displayed only modest JAK1 inhibition.
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http://dx.doi.org/10.1016/j.bmcl.2014.01.001DOI Listing
February 2014

Riluzole prodrugs for melanoma and ALS: design, synthesis, and in vitro metabolic profiling.

Bioorg Med Chem 2012 Sep 21;20(18):5642-8. Epub 2012 Jul 21.

Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Road, Doylestown, PA 18902, USA.

Riluzole (1) is an approved therapeutic for the treatment of ALS and has also demonstrated anti-melanoma activity in metabotropic glutamate GRM1 positive cell lines, a mouse xenograft assay and human clinical trials. Highly variable drug exposure following oral administration among patients, likely due to variable first pass effects from heterogeneous CYP1A2 expression, hinders its clinical use. In an effort to mitigate effects of this clearance pathway and uniformly administer riluzole at efficacious exposure levels, several classes of prodrugs of riluzole were designed, synthesized, and evaluated in multiple in vitro stability assays to predict in vivo drug levels. The optimal prodrug would possess the following profile: stability while transiting the digestive system, stability towards first pass metabolism, and metabolic lability in the plasma releasing riluzole. (S)-O-Benzyl serine derivative 9 was identified as the most promising therapeutically acceptable prodrug.
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http://dx.doi.org/10.1016/j.bmc.2012.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495316PMC
September 2012

Facile Synthesis of Mutagen X (MX): 3-Chloro-4-(dichloromethyl)-5-hydroxy-5H-furan-2-one.

Tetrahedron Lett 2012 Jun;53(25):3144-3146

Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Road, Doylestown, PA 18902, USA.

3-Chloro-4-(dichloromethyl)-5-hydroxy-5H-furan-2-one (Mutagen X, MX) was synthesized in six steps from commercially-available and inexpensive starting materials (27% overall yield). This synthesis enables the preparation of MX analogs and does not require the use of chlorine gas, as do previously reported methods.
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http://dx.doi.org/10.1016/j.tetlet.2012.04.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398704PMC
June 2012

Characterization of a series of 4-aminoquinolines that stimulate caspase-7 mediated cleavage of TDP-43 and inhibit its function.

Biochimie 2012 Sep 29;94(9):1974-81. Epub 2012 May 29.

ALS Biopharma, LLC, Pennsylvania Biotechnology Center, 3805 Old Easton Rd., Doylestown, PA 18902, USA.

Dysfunction of the heterogeneous ribonucleoprotein TAR DNA binding protein 43 (TDP-43) is associated with neurodegeneration in diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we examine the effects of a series of 4-aminoquinolines with affinity for TDP-43 upon caspase-7-induced cleavage of TDP-43 and TDP-43 cellular function. These compounds were mixed inhibitors of biotinylated TG6 binding to TDP-43, binding to both free and occupied TDP-43. Incubation of TDP-43 and caspase-7 in the presence of these compounds stimulated caspase-7 mediated cleavage of TDP-43. This effect was antagonized by the oligonucleotide TG12, prevented by denaturing TDP-43, and exhibited a similar relation of structure to function as for the displacement of bt-TG6 binding to TDP-43. In addition, the compounds did not affect caspase-7 enzyme activity. In human neuroglioma H4 cells, these compounds lowered levels of TDP-43 and increased TDP-43 C-terminal fragments via a caspase-dependent mechanism. Subsequent experiments demonstrated that this was due to induction of caspases 3 and 7 leading to increased PARP cleavage in H4 cells with similar rank order of the potency among the compounds tests for displacement of bt-TG6 binding. Exposure to these compounds also reduced HDAC-6, ATG-7, and increased LC3B, consistent with the effects of TDP-43 siRNA described by other investigators. These data suggest that such compounds may be useful biochemical probes to further understand both the normal and pathological functions of TDP-43, and its cleavage and metabolism promoted by caspases.
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http://dx.doi.org/10.1016/j.biochi.2012.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402613PMC
September 2012

Novel inhibitors of heat shock protein Hsp70-mediated luciferase refolding that bind to DnaJ.

Bioorg Med Chem 2012 Jun 11;20(11):3609-14. Epub 2012 Apr 11.

ALS Biopharma, LLC, Pennsylvania Biotechnology Center, 3805 Old Easton Rd, Doylestown, PA 18902, USA.

Inhibitors of both heat shock proteins Hsp90 and Hsp70 have been identified in assays measuring luciferase refolding containing rabbit reticulocyte lysate or purified chaperone components. Here, we report the discovery of a series of phenoxy-N-arylacetamides that disrupt Hsp70-mediated luciferase refolding by binding to DnaJ, the bacterial homolog of human Hsp40. Inhibitor characterization experiments demonstrated negative cooperativity with respect to DnaJ and luciferase concentration, but varying the concentration of ATP had no effect on potency. Thermal shift analysis suggested a direct interaction with DnaJ, but not with Hsp70. These compounds may be useful tools for studying DnaJ/Hsp40 in various cellular processes.
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http://dx.doi.org/10.1016/j.bmc.2012.03.067DOI Listing
June 2012

Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 Å resolution.

Protein Sci 2011 Apr 1;20(4):670-83. Epub 2011 Mar 1.

Department of Structural Biology, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh and McKean Roads, Spring House, Pennsylvania 19477, USA.

A high-resolution structure of a ligand-bound, soluble form of human monoglyceride lipase (MGL) is presented. The structure highlights a novel conformation of the regulatory lid-domain present in the lipase family as well as the binding mode of a pharmaceutically relevant reversible inhibitor. Analysis of the structure lacking the inhibitor indicates that the closed conformation can accommodate the native substrate 2-arachidonoyl glycerol. A model is proposed in which MGL undergoes conformational and electrostatic changes during the catalytic cycle ultimately resulting in its dissociation from the membrane upon completion of the cycle. In addition, the study outlines a successful approach to transform membrane associated proteins, which tend to aggregate upon purification, into a monomeric and soluble form.
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http://dx.doi.org/10.1002/pro.596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081545PMC
April 2011

Diclofenac potassium liquid-filled soft gelatin capsules for the treatment of postbunionectomy pain.

Curr Med Res Opin 2010 Oct;26(10):2375-84

Premier Research Group, Ltd, Austin, TX 78666, USA.

Objective: Diclofenac potassium liquid-filled soft gelatin capsule (DPSGC) is a rapidly absorbed formulation of diclofenac approved for the treatment of mild to moderate acute pain in adults (≥18 years of age). The objective of this study was to investigate the efficacy and safety of DPSGC 25 mg in a multicenter, randomized, double-blind, placebo-controlled study in patients experiencing pain following first metatarsal bunionectomy.

Research Design And Methods: Patients experiencing a requisite level of pain (≥4 based on an 11-point numeric pain rating scale [NPRS]; 0 = no pain, 10 = worst pain possible) on the day following surgery were randomized to receive DPSGC 25 mg or placebo. Patients received a second dose (remedication) on request or at 8 hours postdose followed by additional doses every 6 hours through the end of postsurgery Day 4. Rescue medication (hydrocodone/acetaminophen) was available as needed after the second dose.

Clinical Trial Registration: NCT00375934.

Main Outcome Measure: The primary efficacy endpoint was the average NPRS score over the 48 hour inpatient multiple-dose period.

Results: DPSGC provided a significant improvement in mean 48 hour NPRS scores over placebo (3.29 vs 5.74, respectively; p < 0.0001), as well as for summed pain intensity difference (203.1 vs 86.6; p < 0.0001). Patients treated with DPSGC experienced a faster onset of meaningful pain relief compared with placebo (p = 0.0034). Rescue medication use on Day 1 and Day 2 was reduced in the DPSGC group compared with placebo (53.5% vs 92.1% on Day 1; 30.3% vs 67.3% on Day 2; p < 0.0001). DPSGC was well tolerated and no patients treated with DPSGC reported serious adverse events. As with any study, there are potential limitations including study design and patient population.

Conclusion: These results indicate that DPSGC reduced pain in patients who underwent bunionectomy and this novel formulation of diclofenac potassium may be a practical option for treating mild to moderate acute pain.
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http://dx.doi.org/10.1185/03007995.2010.515478DOI Listing
October 2010

Diabetogenic effect of a series of tricyclic delta opioid agonists structurally related to cyproheptadine.

Toxicol Sci 2010 Oct 8;117(2):493-504. Epub 2010 Jul 8.

Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477, USA.

The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic β-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog. A review of the literature on the antiserotonergic and antihistaminergic drug cyproheptadine (CPH) and its metabolites revealed shared structural features as well as similar hyperglycemic effects to the present series of DOR agonists. To further evaluate these effects, we established an assay measuring insulin levels in the rat pancreatic β-cell-derived RINm5F cell line, extensively used to study CPH and its metabolites. Like CPH, the initial DOR agonists studied reduced RINm5F cell insulin levels in a concentration-dependent manner. Importantly, compound DOR potency did not correlate with the insulin-reducing potency. Furthermore, the RINm5F cell insulin results correlated with the diabetogenic effect of the compounds in a 5-day mouse study. The RINm5F cell insulin assay enabled the identification of aryl-aryl-amine DOR agonists that lacked an insulin-reducing effect and did not elevate blood glucose in repeated dosing studies conducted over a suprapharmacologic dose range. Thus, not only did the RINm5F cell assay open a path for the further discovery of DOR agonists lacking diabetogenic potential but also it established a reliable, economical, and high-throughput screen for such potential, regardless of chemotype or target pharmacology. The present findings also suggest a mechanistic link between the toxicity observed here and that underlying Wolcott-Rallison Syndrome.
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http://dx.doi.org/10.1093/toxsci/kfq200DOI Listing
October 2010

N-pyridin-3-yl- and N-quinolin-3-yl-benzamides: modulators of human vanilloid receptor 1 (TRPV1).

Bioorg Med Chem Lett 2008 Apr 5;18(8):2730-4. Epub 2008 Mar 5.

Johnson & Johnson Pharmaceutical Research and Development, Research and Early Development, Welsh and McKean Roads, Spring House, PA 19477, USA.

High throughput screening of our compound library revealed a series of N-pyridyl-3-benzamides as low micromolar agonists of the human TRPV1 receptor. Synthesis of analogs in this series led to the discovery of a series of N-quinolin-3-yl-benzamides as low nanomolar antagonists of human TRPV1.
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http://dx.doi.org/10.1016/j.bmcl.2008.02.075DOI Listing
April 2008

Heteroaryl beta-tetralin ureas as novel antagonists of human TRPV1.

Bioorg Med Chem Lett 2007 Nov 12;17(22):6160-3. Epub 2007 Sep 12.

Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Spring House, PA 19477, USA.

We report on a series of alpha-substituted-beta-tetralin-derived and related phenethyl-based isoquinolinyl and hydroxynaphthyl ureas as potent antagonists of the human TRPV1 receptor. The synthesis and Structure-activity relationships (SAR) of the series are described.
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http://dx.doi.org/10.1016/j.bmcl.2007.09.036DOI Listing
November 2007

7-Hydroxynaphthalen-1-yl-urea and -amide antagonists of human vanilloid receptor 1.

Bioorg Med Chem Lett 2004 Jan;14(2):531-4

Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Spring House, PA 19477, USA.

A series of structurally simple 7-hydroxynaphthalenyl ureas and amides were discovered to be potent ligands of human vanilloid receptor 1 (VR1). 1-(7-Hydroxynaphthalen-1-yl)-3-(4-trifluoromethylbenzyl)urea 5f exhibited nanomolar binding affinity (K(i)=1.0nM) and upon capsaicin challenge, behaved as a potent functional antagonist (IC(50)=4nM). The synthesis and structure-activity relationships (SARs) for the series are described.
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http://dx.doi.org/10.1016/j.bmcl.2003.09.090DOI Listing
January 2004

Synthesis and in vitro evaluation of a novel iodinated resiniferatoxin derivative that is an agonist at the human vanilloid VR1 receptor.

Bioorg Med Chem Lett 2002 Apr;12(8):1189-92

Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Spring House, PA 19477, USA.

Using a 'directed' iodination procedure, novel iodo-resiniferatoxin congeners were synthesized from 4-acetoxy-3-methoxyphenylacetic acid and resiniferinol- 9,13,14-ortho-phenylacetate (ROPA). The 2-iodo-4-hydroxy-5-methoxyphenylacetic acid ester of resiniferinol 5 displayed high affinity binding (K(i)=0.71 nM) for the human vanilloid VR1 receptor and functioned as a partial agonist.
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http://dx.doi.org/10.1016/s0960-894x(02)00127-0DOI Listing
April 2002