Jia Zhou, PhD - US grants
Affiliations: | University of Texas Medical Branch, Galveston, TX |
Area:
Medicinal ChemistryWebsite:
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High-probability grants
According to our matching algorithm, Jia Zhou is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
---|---|---|---|---|
2007 — 2008 | Zhou, Jia | R43Activity Code Description: To support projects, limited in time and amount, to establish the technical merit and feasibility of R&D ideas which may ultimately lead to a commercial product(s) or service(s). |
Development of Gsk-3 Beta Inhibitors For the Treatment of Parkinson's Disease @ Psychogenics, Inc. [unreadable] DESCRIPTION (provided by applicant): Parkinson's disease (PD), a chronic and progressive neurological condition and one of aging and age- related diseases, affects approximately 1.5 million people in the US alone. PD not only places severe burden on the patients but also on their family and society. In 2003, approximately US $2.3 billion was spent on drug therapy worldwide to treat Parkinson's disease. Although great strides have been made in the development of agents to treat PD, the existing PD drugs such as dopamine (DA) agonists, levodopa and catechol-O-methyl transferase inhibitors (COMT) only treat the symptoms of the disease, and are also fraught with adverse effects and long-term complications. Consequently, there is a great need for developing disease-modifying and neuroprotective as well as neurorestorative drugs which can slow down or stop the disease from progressing. Recent research suggests that inhibition of the glycogen synthase kinase-3[unreadable] (GSK-3[unreadable]) by small molecules may offer an important strategy in the treatment of a number of neurodegenerative diseases including Alzheimer's disease (AD), but its usefulness in PD has not been described. We have recently found in the cellular and animal MPTP model of parkinsonism, an induction in the hyperphosphorylated form of Tau, p-Tau, with hyperphosphorylation seen at many sites, including those found in neurofibrillary tangles of AD. The increase in p-Tau levels was strictly dependent upon the presence of a- Syn. This requirement for a-Syn was mandatory, since in a-Syn-/- mice, and in transfected cells not expressing any a-Syn, the toxin failed to induce p-Tau. MPTP also caused an increase in a-Syn protein levels. Hyperphosphorylation of Tau lead to its dissociation from the cytoskeleton, and aggregates of p-Tau were seen in sarkosyl-insoluble and Triton X-100-insoluble fractions. a-Syn was able to form stable heteromeric protein complexes with p-Tau, and p-Tau aggregates were seen in mature inclusion bodies of a-Syn. MPP+ caused the activation of several p-Tau-specific kinases, such as GSK-3[unreadable] and p-ERK. Blockade of GSK-3[unreadable] not only prevented, but also reduced, MPP+-induced p-Tau formation, a-Syn accumulation and cytotoxicity. Very new data obtained in human postmortem PD brains, in collaboration with Dr. Jeffrey Joyce, show a similar pattern of pathology: increased a-Syn accumulation, hyperphosphorylation of Tau at sites similar to the MPTP models [pSer262 and pSer396/404], lack of phosphorylation at sites not seen with MPTP [pSer202], and large increases in GSK-3[unreadable]. Interestingly, these pathological changes were further augmented in PD patients with dementia [PD + DEM]. Together, these findings in PD brains confirm the validity of our findings with the MPTP models. Importantly, prior to our findings, a possible role for GSK-3[unreadable] in PD has not been previously described, although its role in AD is well studied. In addition to our findings, another study found strong linkage of two single nucleotide polymorphisms in the GSK-3[unreadable] gene to sporadic PD. Thus, GSK-3[unreadable] presents a novel target site in the development of novel therapies for PD. To date, we have identified some nM potency GSK-3[unreadable] inhibitors that emerged from our SAR studies of staurosporine. A number of these designed staurosporine analogs have been screened against a family of 30 kinases. Among the compounds tested we found one, an indolyl-indazolylmaleimide, that was able to inhibit 98% of the kinase activity of GSK-3[unreadable] when tested at a concentration of 10 [unreadable]M. After further structural modifications described below, novel 3-(indol-3-yl)-4-(benzofuran-3-yl)maleimides having a Ki value as low as 2 nM selectively against GSK-3[unreadable] relative to 30 additional kinases were identified. Moreover, we have been able to show that some of these ligands are able to exert a neuroprotective and neurorestorative action in vitro. The ultimate goal would be to identify one or two GSK-3[unreadable] inhibitors that could be further developed for slowing or halting the progression of PD. Through funding from this STTR grant, we intend to follow-up on the exciting preliminary findings we have made in pursuit of novel GSK-3[unreadable] inhibitors as potential therapeutics for the treatment of PD. To achieve this goal, the Specific Aims of this research proposal are as follows: 1. Compound selection and synthesis: Based upon the compound library in hand, 10 potent GSK- 3[unreadable] inhibitors will be resynthesized for further in vitro pharmacological studies. Then 2 or 3 of the most promising ligands based upon the in vitro profile will be scaled up (about 5 grams each) for in vivo animal studies. 2. Neuroprotective In vitro studies in transfected cells and neurons: Investigation of time course and dose response of the compounds for inhibition of GSK-3[unreadable], analyses of other kinases and phosphatases that are modulated by these compounds, and comparison of our findings with the effects using lithium. 3. Neurorestorative in vitro studies in transfected cells and neurons: After the initiation of cytotoxicity, we will examine the time and dose of GSK-3[unreadable] inhibitors necessary for neurorestoration. 4. In vivo animal studies: Injection with MPTP for 5 days will be followed by simultaneous or delayed injections with increasing doses of the GSK-3[unreadable] inhibitors for different time periods. GSK-3[unreadable], a-Syn, Tau, kinases and phosphatases will be examined, as specified in Specific Aims 2 and 3. Key words: GSK-3[unreadable] inhibitors, Kinases, Selectivity, Parkinson's disease, Therapeutics, Staurosporine analogs, Neuroprotective agents, Neurorestorative agents, Neuroprotection, a-Synuclein, p-Tau, Taupathies, Synucleopathies, MPTP model, Aging, Neurodegenerative, Age-related diseases, Alzheimer's disease. Project Des inson's disease (PD), the second most common neurodegenerative disease next to Alzheimer's disease (AD), is a progressive neurological condition associated with aging. Our proposal entails the chemical synthesis of novel staurosporine analogues as potent glycogen synthase kinase-3[unreadable] (GSK-3[unreadable]) inhibitors, and in vitro studies in transfected cells and neurons as well as in vivo studies in animals of these compounds, which have the great potential to be developed as neuroprotective and neurorestorative therapies to slow down or stop Parkinson's disease from progressing. Public Health [unreadable] [unreadable] [unreadable] |
0.904 |
2008 | Zhou, Jia | R43Activity Code Description: To support projects, limited in time and amount, to establish the technical merit and feasibility of R&D ideas which may ultimately lead to a commercial product(s) or service(s). |
Naag Peptidase Inhibitors For the Treatment of Traumatic Brain Injury @ Psychogenics, Inc. [unreadable] DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a serious public health concern. It is estimated that severe TBI will become the third most common cause of death and disability globally by the year 2020. An estimated 1.5 million persons sustain a TBI in the United States annually resulting in more than 230,000 hospitalizations and 50,000 deaths. The annual economic cost to society for the care of head-injured patients has been estimated to exceed $25 billion. In particular, there is a desperate need to have therapeutic agents available to treat head injuries that occur in large numbers among US troops engaged in combat. However, no truly efficacious and approved therapies are currently available for the treatment of TBI. Glutamate-receptor-mediated cell injury acts as an important mechanism of secondary brain damage after TBI. NAAG peptidases (GCPII and III) are extracellular enzymes that hydrolyze N-acetylaspartylglutamate (NAAG) to N-acetylaspartate (NAA) and glutamate (Glu) following the release of the peptide into the synaptic space. Inhibition of GCPII and III increases NAAG levels with the consequent activation of presynaptic group II mGluRs and inhibition of transmitter release including glutamate. These actions have the potential to provide neuroprotection in clinical conditions in which Glu mediates and mGluR3 activation reduces clinical pathology. To date, our research team has identified a number of urea-based compounds including ZJ 43, ZJ 11 and ZJ 17 as NAAG peptidase inhibitors with nM potency after extensive structure activity relationship studies. Data from animal studies have demonstrated that administration of ZJ 43 represents a potential novel strategy to provide neuroprotection after TBI. However, there exists an important concern that these compounds are too polar to readily penetrate the blood-brain barrier (BBB). The development of prodrugs will provide the means for precise dose delivery to the brain as well as the use of lower dose ranges that obviate the problem of unwanted systemic side effects. The long-term goal of this research project is to develop these NAAG peptidase inhibitors as novel therapeutics for TBI. In order to accelerate the development and application of these compounds for human clinical trials, the immediate goal of this research proposal is to develop novel prodrugs to improve the BBB penetration capabilities of our candidate NAAG peptidase inhibitors. It is noteworthy that our very recent preliminary data have demonstrated that one mono-ester prodrug of ZJ 43 is three-fold more active than the parent drug ZJ 43 in Fmr1 knockout mouse models of fragile X syndrome and autism. All these preliminary findings encouraged us to pursue extensive studies on the design, synthesis and pharmacological investigation of prodrugs of our NAAG peptidase inhibitors. Through funding from this two- year SBIR grant, we intend to bring our discovery of the efficacy of NAAG peptidase inhibitors in animal models of TBI to a higher level of preclinical development and ultimately to foster the translation of this concept into clinical trials. Specific Aim 1: Synthesis of compounds: Rational design and synthesis of new prodrug forms of lead NAAG peptidase inhibitors. Based upon the structures of our lead NAAG peptidase inhibitors and the successful results achieved for some commercial prodrugs, ten prodrugs including seven mono-ester or amide prodrugs and three 1,4-dihydropyridine prodrugs of the current best drug candidates ZJ 43, ZJ 11, and ZJ 17 will be synthesized for the testing described in Aim 2. In addition, 1.0 gram each of the above three parent NAAG peptidase inhibitors will be prepared as reference compounds for the studies of their prodrugs for the purpose of efficacy comparison. Specific Aim 2: Pharmacological studies of the above prodrugs: Testing of above compounds using an in vivo TBI model. The prodrugs identified in Aim 1 will be tested for cellular protection in a well- characterized and clinically relevant rat model of TBI. Each of the ten prodrugs from Aim 1 will be evaluated in a dose-dependent design in which drugs are administered systemically after TBI. Drug efficacy for reducing neuronal cell death will be evaluated at 24 hours after TBI using histofluorescence with advanced stereological cell counting techniques. The three most efficacious prodrugs for reducing acute cell death will be scaled up and undergo further in vivo functional testing to determine their efficacy for reducing motor and cognitive behavioral deficits associated with TBI. [unreadable] [unreadable] Key words: NAAG peptidase inhibitors, Traumatic brain injury, Head injury, Therapeutics, NAAG, GCP II, GCP III, Glutamate, Neurotransmitters, Excessive glutamatergic transmission, mGluRs, mGluR3, Prodrug, Mono-ester, Mono-amide, 1,4-Dihydropyridine, Drug delivery system, Blood-brain barrier, TBI model, CNS disorders, Neuroprotection.Traumatic brain injury (TBI) is a serious public health concern, and estimated to become the third most common cause of death and disability globally. Our proposal entails the chemical design and synthesis of novel NAAG peptidase inhibitors and their prodrugs, as well as in vivo TBI pharmacological studies of these compounds, which have the great potential to be developed as therapeutics for the treatment of traumatic brain injury. [unreadable] [unreadable] [unreadable] |
0.904 |
2008 | Zhou, Jia | R43Activity Code Description: To support projects, limited in time and amount, to establish the technical merit and feasibility of R&D ideas which may ultimately lead to a commercial product(s) or service(s). |
Prodrugs of Naag Peptidase Inhibitors For the Treatment of Schizophrenia @ Psychogenics, Inc. [unreadable] DESCRIPTION (provided by applicant): Schizophrenia is a chronic, severe, and disabling brain disease. Nearly 1 percent of the population develops schizophrenia during their lifetime - more than 2 million Americans suffer from this disease in a given year. The schizophrenia world market generated total revenues of nearly $12 billion in 2004 and is still growing steadily. Atypical antipsychotic drugs, such as clozapine, risperidone, and olanzapine are widely used to treat schizophrenia but are not fully effective in moderating the positive, negative and cognitive symptoms that different patients present. These drugs act primarily via antagonism of dopamine and serotonin receptors. However, a substantial literature supports the involvement of glutamatergic circuits in mediating the symptoms of schizophrenia in humans and animal models of this disorder. As a result, glutamate receptor ligands are under active analysis as potential alternative and adjuvant therapy for the treatment of this disorder. Among these are activators of the glycine site on the NMDA receptor and group II metabotropic glutamate receptor (mGluR) agonists. N-Acetylaspartylglutamate (NAAG) is the third most prevalent transmitter in the mammalian nervous system and a group II mGluR (mGluR3>>mGluR2) selective agonist. It is inactivated by extracellular peptidases (GCPII and III) to N-acetylaspartate (NAA) and glutamate (Glu) following the release of the peptide into the synaptic space. Inhibition of GCPII and III increases NAAG levels with the consequent activation of presynaptic group II mGluRs. Group II mGluR activation inhibits the release of glutamate and reduces the schizophrenia-like behavioral symptoms elicited by phencyclidine (PCP). Our research team demonstrated that NAAG peptidase inhibition and subsequent group II mGluR activation by NAAG also reduces these behaviors and thus potentially represents a new therapeutic approach to schizophrenia and acute PCP intoxication. After extensive SAR studies, our research team has identified a number of urea-based compounds, including ZJ 43, ZJ 11 and ZJ 17, as NAAG peptidase inhibitors with nanomolar potency. Systemic administration of the NAAG peptidase inhibitor ZJ 43 reduces PCP-induced behaviors in a rat model of schizophrenia, and this action of ZJ 43 is blocked by the group II mGluR antagonist LY341495. However, there exists an important concern that these compounds are too polar to readily penetrate the blood-brain barrier (BBB) and to advance to human clinical studies. The development of prodrugs will provide the means for precise dose delivery to the brain to improve their efficacy as well as the use of lower dose ranges that obviate the problem of unwanted systemic side effects. The long-term goal of this research project is to develop these NAAG peptidase inhibitors as novel therapeutics or adjuvant therapies for schizophrenia. In order to accelerate the development and application of these compounds for human clinical trials, the immediate goal of this research proposal is to develop novel prodrugs to improve the BBB penetration capabilities of our candidate NAAG peptidase inhibitors to improve their efficacy. It is noteworthy that our very recent preliminary data have demonstrated that one mono-ester prodrug of ZJ 43 is about 7-fold more active than the parent drug ZJ 43 in our PCP-induced behavioral model of schizophrenia. These findings encouraged us to pursue further studies on the design, synthesis and pharmacological investigation of prodrugs of our NAAG peptidase inhibitors. Through funding from this SBIR Phase I grant, we intend to bring our discovery of the efficacy of NAAG peptidase inhibitors in animal models of schizophrenia to a higher level of preclinical development and ultimately to foster the translation of this concept into clinical trials. Specific Aim 1: Synthesis of compounds: Rational design and synthesis of new prodrug forms of lead NAAG peptidase inhibitors. Based upon the structures of our NAAG peptidase inhibitors and the successful results achieved for some commercial prodrugs, thirteen prodrugs including mono-ester and -amide prodrugs of the current best drug candidates ZJ 43, ZJ 11, and ZJ 17 will be synthesized for the testing described in Aim 2. In addition, 1.0 gram each of the NAAG peptidase inhibtors ZJ 43, ZJ 11, and ZJ 17 will be prepared as reference compounds for the purpose of efficacy comparison during the studies of their prodrugs. Specific Aim 2: Characterization of the efficacy of the above prodrugs of NAAG peptidase inhibitors in vivo, including PCP-induced behavioral models of schizophrenia (Aim 2.1); For the behaviorally most effective prodrugs: definition of the level of NAAG peptidase inhibition that they produce in vivo (Aim 2.2); Direct measurement of the levels of the prodrugs and active inhibitors in the brain (Aim 2.3); Determination if the prodrugs have any inherent activity as peptidase inhibitors or group II mGluR agonists (Aim 2.4). PUBLIC HEALTH RELEVANCE: Schizophrenia is a chronic, severe, and disabling brain disease. Through funding from this two-year SBIR Phase I grant, we intend to bring our discovery of the efficacy of NAAG peptidase inhibitors and their novel prodrugs in animal models of schizophrenia to a higher level of preclinical development and ultimately to foster the translation of this concept into clinical trials for the treatment of schizophrenia. [unreadable] [unreadable] [unreadable] |
0.904 |
2012 — 2013 | Cunningham, Kathryn A. Zhou, Jia |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Optimization of Allosteric Modulators of 5-Ht2c Receptor @ University of Texas Medical Br Galveston DESCRIPTION (provided by applicant): The modulation of 5-HT2C receptor (5-HT2CR) function holds a tremendous amount of therapeutic promise for the treatment of diseases of significant unmet medical need, including addiction, anxiety, depression, obesity/eating disorders and schizophrenia. Successful development of 5-HT2CR ligands requires selectivity versus the highly homologous 5-HT2AR and 5-HT2BR, because agonism at these receptors can result in serious CNS and cardiovascular adverse events. The rationale for this proposal is that allosteric modulators of the 5-HT2CR present a unique drug design strategy to augment the response to endogenous 5-HT in a site- and event-specific manner. This novel approach of using allosteric modulators of the 5-HT2CR to develop novel probes and therapeutics is very attractive since it is much easier to achieve high receptor subtype selectivity or even absolute specificity with a ligand binding to the allosteric site than with orthosteric ligands that bind to the endogenous ligand binding site. To date only one compound, PNU-69176E, has been identified via the compound library screening as a 5-HT2CR allosteric modulator. However, the relevant structure-activity relationship (SAR) studies were sparse, and thus our knowledge in this regard is quite limited. Our objective in this application is to optimize and develop allosteric modulators of the 5-HT2CR to generate novel, highly selective and potent 5-HT2CR ligands that will act as small molecule probes for the nervous system and novel therapeutics for CNS disorders. To accomplish this objective, we plan to pursue the following two specific aims: 1) Chemical synthesis and optimization of small molecules based on PNU-69176E as the chemical lead; and 2) Biological characterization of newly synthesized compounds using a cell-based signaling assay to identify allosteric modulators of 5-HT2CR with high potency, selectivity and better drug-like properties. This project is innovative, potentially high impact research that will aid in elucidating information about the chemical neurobiology of allosteric modulation of 5-HT2CR. Our results are expected to provide the valuable SAR and novel mechanistic insight into these chemically unique allosteric modulators of 5-HT2CR.The proposed studies will identify small molecules that will be utilized to probe the neurobiology of the 5-HT2CR. The long term goal of this project is to develop these modulators for preclinical validation and clinical application in translational research and ultimately as novel therapeutic candidates. PUBLIC HEALTH RELEVANCE: This research project is highly relevant to public health because it entails chemical synthesis, optimization and pharmacological investigation of novel allosteric modulators of the 5-HT2C receptor that will act as small molecule probes for nervous system and novel therapeutics for a variety of CNS disorders of significant unmet medical need. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing new medications and fundamental knowledge that will help to lengthen life and to reduce the burdens of illness. |
0.984 |
2013 — 2015 | Cheng, Xiaodong [⬀] Zhou, Jia |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Novel Pharmacological Probes Targeting Exchange Proteins Activated by Camp (Epac) @ University of Texas Medical Br Galveston DESCRIPTION (provided by applicant): This is an R01 application in response to FOA PAR-12-060 Solicitation of Validated Hits for the Discovery of in vivo Chemical Probe (R01). cAMP-mediated cell signaling regulates a myriad of important biological processes and plays important roles in the development of many human diseases. In eukaryotic cells, the effects of cAMP are mainly transduced by two groups of intracellular cAMP receptors, the classic protein kinase A/cAMP-dependent protein kinase (PKA/cAPK) and a new family of more recently discovered exchange proteins directly activated by cAMP/cAMP-regulated guanine nucleotide exchange factor (EPACs/cAMP-GEFs). One of the major challenges within the research field is the lack of EPAC specific antagonists for interrogating the biological functions of EPACs in physiological setting and for understanding of disease mechanisms in which EPACs are implicated. To bridge this gap, we have identified and validated several novel, first-in-class small chemical antagonists specific for EPACs. In the present proposal, we will build on the validated hits discovered in our laboratory as the lead candidates and design, synthesize and evaluate more potent and specific EPAC specific probes. Optimized EPAC chemical probes that effectively inhibit EPAC signaling in biochemical and cell-based assays will be analyzed in vivo in animal models to identify potential target molecules for development of EPAC-based therapeutics. The proposed studies build upon an ongoing, proven productive collaboration between two principal investigators with extensive complimentary expertise in EPAC/cAMP biology and medicinal chemistry, respectively. The interdisciplinary perspectives, new chemical entities and emerging medical importance of EPAC will lead to the discovery of a new class of in vivo chemical probes that can be used in studying disease mechanisms and treatments related to EPAC signaling. |
0.984 |
2013 — 2015 | Rudra, Jai Zhou, Jia |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Synthetic Nanofiber Vaccines For Cocaine Addiction @ University of Texas Medical Br Galveston DESCRIPTION (provided by applicant): Cocaine addiction is second only to opiates as the most problematic drug in the Americas with an enormous fee in human tragedy as well as in public health and safety. Currently there is no FDA approved pharmacological therapy for cocaine addiction, which has prompted the development of immuno-prophylactic alternatives. A therapeutic vaccine that elicits anti-cocaine antibodies will allow the rapid sequestration of the drug in circulation and reduce the amount and rate of its entry into the brain. A limiting factor t the success of small molecule drug vaccines is the low degree of immunity evoked by the addictive drug analog and lack of effective yet safe immune adjuvants. Also, clinical studies have unambiguously demonstrated that the design of proper haptens is critical for proper immune stimulation both in terms of amount of antibody elicited and antibody specificity. The goals of this proposal are to design and develop cocaine vaccines based on designed cocaine analogs in combination with a peptide nanofiber-based delivery platform for eliciting high titers of anti-cocaine antibodies and test their efficacy in a mouse motor activity assay. The work is divided into two aims: Aim 1) Design and synthesis of self-assembling peptide nanofiber-based cocaine vaccines. Aim 2) Test the efficacy of peptide nanofiber cocaine vaccine formulations in a mouse model. Our approach will be to design and chemically synthesize peptide nanofiber vaccines against cocaine. In aim 1, we will synthesize novel cocaine-based small molecule haptens modified at the P3 site with various chemical linkers and linker lengths. We will then conjugate the haptens to a self-assembling peptide domain using an orthogonal chemistry to produce peptide nanofibers that display the haptens in a multivalent fashion. In aim 2, we will investigate antibody responses against modified cocaine haptens coupled self-assembling peptides and the effect of linker chemistry and linker-length on the antibody titers. Mice will be immunized with synthetic cocaine nanofiber vaccines and the production of anti-cocaine antibodies will be investigated using a prime-boost regimen. Formulations that elicit high titers o anti-cocaine antibodies will be investigated for suppression of acute cocaine-induced motor activity and cocaine-induced behavioral sensitization. Success in these studies will provide us with insights into the development of small molecule drug analogs suitable for vaccination and the utility of self-assembling peptides as adjuvants for vaccines to treat addiction. Also, more broadly, completion of the proposed work will integrate the fields of synthetic chemistry, nanotechnology, immunology, and addiction to significantly impact human health. |
0.984 |
2015 — 2019 | Cunningham, Kathryn A. Zhou, Jia |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
5?Ht2cr Allosteric Modulators as Novel Pharmacotherapy in Cocaine Use Disorder @ University of Texas Medical Br Galveston ? DESCRIPTION (provided by applicant): Cocaine use disorder remains a significant health problem in the United States, and effective and safe pharmacotherapeutic approaches are urgently needed to maximize treatment success and minimize lapses to drug use. The cycling course of cocaine use disorder is tied to a multitude of behavioral and cognitive processes with impulsivity (rapid unplanned reactions to stimuli without regard for the consequences) and cue reactivity (attentional bias toward cocaine-associated cues) cited as two key phenotypes that set up vulnerability to relapse even years into recovery. The serotonin (5-HT) system provides modulatory control over impulsivity and cue reactivity, particularly through the G protein-coupled 5-HT2C receptor (5-HT2CR). Data suggest that dampened 5- HT2CR signaling capacity may contribute to phenotypic vulnerability to relapse and that normalization of 5-HT2CR tone may be useful to suppress relapse promoted by impulsivity and cue reactivity. We hypothesize that a small molecule positive allosteric modulator (PAM) of the 5-HT2CR that augments the response to endogenous 5-HT and/or an exogenous 5-HT2CR orthosteric ligand is a novel strategy to restore 5-HT2CR function. The present grant is built upon our progress in the rational design, synthesis and pharmacological evaluation of new chemical entities based upon the only reported selective 5-HT2CR PAM PNU-69176E. We have synthesized new small molecules (e.g., CYD-1-79, CYD-3-30, CYD-6-16-2) which exhibit initial profiles as 5-HT2CR PAMs (functional signaling in live cells, radioligand binding assays) and reasonable oral and brain bioavailability. In vivo behavioral studies demonstrated that CYD-1-79, at doses that do not affect general motor activity, enhanced the effects of a selective 5-HT2CR agonist in drug discrimination analyses, and suppressed impulsivity and cue reactivity in rats, indicating efficacy in primary animal models pertinent to relapse in cocaine use disorder. Our objective is to optimize 5-HT2CR PAMs with a favorable drug metabolism and pharmacokinetics (DMPK) profile, and analyze select molecules in proof-of-concept behavioral models to support therapeutic potential for cocaine use disorder. To accomplish our objective, we will: (1) design, synthesize and optimize 5-HT2CR PAMs; (2) define selectivity and specificity and DMPK profiles of 5-HT2CR PAMs in vitro; and (3) determine DMPK in vivo and efficacy of optimized 5-HT2CR PAMs in rodent models of impulsivity and cue reactivity. This innovative, potentially high impact small molecule development project will elucidate important new information about the chemical neurobiology of 5-HT2CR allosteric modulation, and drive new concepts and directions in cocaine use disorder and anti-relapse medications. |
0.984 |
2016 — 2020 | Nestler, Eric J. (co-PI) [⬀] Rudenko, Gabrielle Zhou, Jia |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Small Molecule Modulators of ?Fosb Function @ University of Texas Medical Br Galveston PROJECT SUMMARY There is an urgent need for novel therapeutics to treat drug addiction. One potential novel drug target that plays a key role in this devastating disorder is ?FosB. ?FosB accumulates in highly specific regions of the brain (in particular the nucleus accumbens) in response to cocaine or other drugs of abuse. ?FosB mediates increases in drug-seeking behavior seen after prior drug exposure. As a transcription factor, ?FosB regulates the expression of many genes crucial to drug addiction, including the AMPA glutamate receptor subunit GluA2 and cyclin-dependent kinase 5 (Cdk5). ?FosB can both repress and activate gene transcription, but the molecular basis of this dual action is not known. One explanation is that ?FosB forms both heterodimers with JunD as well as homodimers with itself, and that these two ?FosB-containing species differentially regulate gene transcription. We seek to validate the therapeutic potential of ?FosB, and to delineate its molecular mechanisms. To this end, our goal is to leverage compounds that target ?FosB species in vivo. We hypothesize that, by regulating ?FosB with small molecules, we can exploit ?FosB to strategically regulate key genes and overcome harmful neuronal and behavioral adaptations induced by chronic cocaine. Our approach is to develop potent in vivo chemical probes that target ?FosB and discriminate between ?FosB homodimers and heterodimers. We demonstrated with first generation scaffolds that pharmacologically targeting ?FosB elicited biological and behavioral responses in mice chronically treated with cocaine. We have now identified new scaffolds with more drug-like properties, but low micromolar activity, which we have validated in vitro. We propose to: 1) improve the potency of our probes through chemical optimization and iterative testing, 2) demonstrate that our compounds directly bind ?FosB and reveal their mechanism-of-action using structural biology, and 3) measure the impact of our probes in vivo both on the behavioral responses to cocaine, and on the transcription of GluA2 and Cdk5. The rationale for this proposal is that improved probes will enable us to test the therapeutic potential of ?FosB as a viable drug target to ameliorate aspects of drug addiction. In addition, our improved probes will enable us to delineate aspects of ?FosB in vivo (in particular the role of ?FosB homodimers vs. heterodimers). This proposal is innovative because it will yield chemical tools for a novel and non-traditional putative therapeutic target for which no probes are currently available. Importantly, we will be able to test whether ?FosB can be used as a conduit to safely regulate specific genes that maintain the addicted state by harnessing the highly region-specific accumulation of ?FosB in the nucleus accumbens in response to drugs of abuse. Furthermore, our probes will enable us to reveal completely new mechanistic information on ?FosB which cannot be easily gained using current techniques. This information is very significant because it could reveal completely novel strategies to treat drug addiction. |
0.984 |
2018 | Cunningham, Kathryn A. Zhou, Jia |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
5-Ht2cr Allosteric Modulators as Novel Pharmacotherapy in Cocaine Use Disorder @ University of Texas Med Br Galveston Contact PD/PI: Zhou, Jia ABSTRACT Cocaine use disorder remains a significant health problem in the United States, and effective and safe pharmacotherapeutic approaches are urgently needed to maximize treatment success and minimize lapses to drug use. The cycling course of cocaine use disorder is tied to a multitude of behavioral and cognitive processes with impulsivity (rapid unplanned reactions to stimuli without regard for the consequences) and cue reactivity (attentional bias toward cocaine-associated cues) cited as two key phenotypes that set up vulnerability to relapse even years into recovery. The serotonin (5-HT) system provides modulatory control over impulsivity and cue reactivity, particularly through the G protein-coupled 5-HT2C receptor (5-HT2CR). Data suggest that dampened 5- HT2CR signaling capacity may contribute to phenotypic vulnerability to relapse and that normalization of 5-HT2CR tone may be useful to suppress relapse promoted by impulsivity and cue reactivity. We hypothesize that a small molecule positive allosteric modulator (PAM) of the 5-HT2CR that augments the response to endogenous 5-HT and/or an exogenous 5-HT2CR orthosteric ligand is a novel strategy to restore 5-HT2CR function. The present grant is built upon our progress in the rational design, synthesis and pharmacological evaluation of new chemical entities based upon the only reported selective 5-HT2CR PAM PNU-69176E. We have synthesized new small molecules (e.g., CYD-1-79, CYD-3-30, CYD-6-16-2) which exhibit initial profiles as 5-HT2CR PAMs (functional signaling in live cells, radioligand binding assays) and reasonable oral and brain bioavailability. In vivo behavioral studies demonstrated that CYD-1-79, at doses that do not affect general motor activity, enhanced the effects of a selective 5-HT2CR agonist in drug discrimination analyses, and suppressed impulsivity and cue reactivity in rats, indicating efficacy in primary animal models pertinent to relapse in cocaine use disorder. Our objective is to optimize 5-HT2CR PAMs with a favorable drug metabolism and pharmacokinetics (DMPK) profile, and analyze select molecules in proof-of-concept behavioral models to support therapeutic potential for cocaine use disorder. To accomplish our objective, we will: (1) design, synthesize and optimize 5-HT2CR PAMs; (2) define selectivity and specificity and DMPK profiles of 5-HT2CR PAMs in vitro; and (3) determine DMPK in vivo and efficacy of optimized 5-HT2CR PAMs in rodent models of impulsivity and cue reactivity. This innovative, potentially high impact small molecule development project will elucidate important new information about the chemical neurobiology of 5-HT2CR allosteric modulation, and drive new concepts and directions in cocaine use disorder and anti-relapse medications. Project Summary/Abstract Page 6 |
0.97 |
2021 | Nestler, Eric J. (co-PI) [⬀] Robison, Alfred J Rudenko, Gabrielle Zhou, Jia |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Small Molecule Modulators of ?Fosb @ University of Texas Med Br Galveston PROJECT SUMMARY There is an urgent need to develop effective strategies to combat drug addiction, a major public health burden. Unfortunately, current efforts are hampered by a focus on a very limited range of drug targets. Decades of work have established that the transcription factor DFosB plays a critical role in drug addictive behaviors in rodent models, with validation in humans available as well. In response to chronic cocaine or opioids (e.g., heroin) administration, DFosB mediates aspects of drug seeking, reward, self-administration, and relapse. Due to its unusual stability, DFosB accumulates to very high levels in the brain in regions critical for reward, making it an attractive target for addiction therapies. However, critical mechanistic aspects of DFosB function are not known, making it difficult to pursue DFosB as a therapeutic target. It is not known how DFosB molecules are arranged in vivo, what molecular features control their ability to bind to DNA and turn genes on or off, and whether these features can be targeted strategically with small molecules in order to regulate DFosB function in vivo to combat drug use disorders. We hypothesize that, by modulating ?FosB with small molecules, we can selectively regulate key strategic DFosB gene targets, and thereby the long-term neural and behavioral adaptations that DFosB triggers in response to chronic drug use. To test our hypotheses, we propose to 1) optimize a series of validated lead compounds into high-affinity chemical probes targeting DFosB in vitro and in vivo; 2) unravel how key molecular features in DFosB regulate its actions; and 3) determine how targeting these features either with our chemical probes or novel genetic tools alters behaviors in animal models of addiction. To this end, we have an outstanding translational research team overseeing a robust and effective experimental platform that draws on our prior combined work. We have already achieved important milestones. First, we have discovered that DFosB partners not only with JunD but also with itself in order to bind DNA, and these two species are structurally and functionally very different. Second, we have uncovered a molecular switch in ?FosB that controls its binding to DNA and that works differently in heteromeric vs. homomeric ?FosB complexes. Third, we have developed a large panel of lead compounds that target DFosB and that we can leverage to gain both fundamental mechanistic insight into DFosB function, as well as assess their in vivo effects on addictive behaviors. Together, our work creates a powerful, previously unavailable, and highly actionable platform to test the utility of DFosB as a therapeutic target. The positive impact of this work will be to further de-risk DFosB as a therapeutic target by creating comprehensive, mechanism-based knowledge onto which a drug discovery program will be anchored, focused on a completely novel target to combat addiction. This innovative proposal will provide novel insight into the pathophysiology of drug addiction, and novel chemical probes validated in cells and animal models, which together will serve as a strong platform from which to target DFosB for therapeutic or diagnostic purposes. |
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