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Daga P.R.,Astraea Therapeutics, Llc | Zaveri N.T.,Astraea Therapeutics, Llc
Proteins: Structure, Function and Bioinformatics | Year: 2012

The opioid receptor-like receptor, also known as the nociceptin receptor (NOP), is a class A G protein-coupled receptor (GPCR) in the opioid receptor family. Although NOP shares a significant homology with the other opioid receptors, it does not bind known opioid ligands and has been shown to have a distinct mechanism of activation compared to the closely related opioid receptors mu, delta, and kappa. Previously reported homology models of the NOP receptor, based on the inactive-state GPCR crystal structures, give limited information on the activation and selectivity features of this fourth member of the opioid receptor family. We report here the first active-state homology model of the NOP receptor based on the opsin GPCR crystal structure. An inactive-state homology model of NOP was also built using a multiple template approach. Molecular dynamics simulation of the active-state NOP model and comparison to the inactive-state model suggest that NOP activation involves movements of transmembrane (TM)3 and TM6 and several activation microswitches, consistent with GPCR activation. Docking of the selective nonpeptidic NOP agonist ligand Ro 64-6198 into the active-state model reveals active-site residues in NOP that play a role in the high selectivity of this ligand for NOP over the other opioid receptors. Docking the shortest active fragment of endogenous agonist nociceptin/orphaninFQ (residues 1-13) shows that the NOP extracellular loop 2 (EL2) loop interacts with the positively charged residues (8-13) of N/OFQ. Both agonists show extensive polar interactions with residues at the extracellular end of the TM domain and EL2 loop, suggesting agonist-induced reorganization of polar networks, during receptor activation. © 2012 Wiley Periodicals, Inc.


Journigan V.B.,Astraea Therapeutics, Llc | Zaveri N.T.,Astraea Therapeutics, Llc
Life Sciences | Year: 2013

Since the discovery of the TRPM8 gene in 2001, the TRPM8 ion channel, better known as the 'cold receptor' has been the target of a significant effort from the pharmaceutical industry to produce small-molecule agonists and antagonists of this receptor for various therapeutic applications ranging from cancer and urological disorders to the treatment of cold hypersensitivity and pain. Recently, a number of clinical studies have implicated menthol, the natural ligand of TRPM8, in facilitating and maintaining cigarette smoking behavior, possibly through its counter-irritant effects. However, a pharmacological link between menthol's action via TRPM8 and nicotine addiction has not been yet been investigated. This review gives an overview of reported small-molecule TRPM8 agonists and antagonists and discusses their efficacy in models of various disease states. These compounds may be useful pharmacological tools to investigate the effect of menthol on nicotine addiction. © 2012 Elsevier Inc.


In the two decades since the discovery of the nociceptin opioid receptor (NOP) and its ligand, nociceptin/orphaninFQ (N/OFQ), steady progress has been achieved in understanding the pharmacology of this fourth opioid receptor/peptide system, aided by genetic and pharmacologic approaches. This research spawned an explosion of small-molecule NOP receptor ligands from discovery programs in major pharmaceutical companies. NOP agonists have been investigated for their efficacy in preclinical models of anxiety, cough, substance abuse, pain (spinal and peripheral), and urinary incontinence, whereas NOP antagonists have been investigated for treatment of pain, depression, and motor symptoms in Parkinson's disease. Translation of preclinical findings into the clinic is guided by PET and receptor occupancy studies, particularly for NOP antagonists. Recent progress in preclinical NOP research suggests that NOP agonists may have clinical utility for pain treatment and substance abuse pharmacotherapy. This review discusses the progress toward validating the NOP-N/OFQ system as a therapeutic target. © 2016 American Chemical Society.


Patent
University of Minnesota and Astraea Therapeutics, Llc | Date: 2013-08-14

The present invention relates to a method for the management of pain associated with sickle cell disease. In particular, the method comprises administering to a patient in need of such pain management a therapeutically effective amount of a nociceptin (NOP) receptor agonist or an NOP receptor agonist/mu opioid receptor (MOR) partial agonist.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 760.01K | Year: 2016

DESCRIPTION provided by applicant Every year about million adult Americans experience some form of pain a condition that costs the nation between $ billion and $ billion annually in lost productivity and treatment The recently released `National Pain Strategyandapos developed by the NINDSandapos s IPRCC recognizes acute and chronic pain as a serious and costly public health issue and articulates that new treatment approaches need to be developed to reduce the burden of pain in the US Opioid analgesics are the mainstay of pain treatment and often the only treatment option that provides significant relief However opioid analgesics which are mainly mu opioid receptor MOP agonists are controlled substances that have abuse potential and are riddled with other side effects such as constipation nausea and tolerance which impede their long term safety and effectiveness There is clearly a need for new analgesics that provide opioid like efficacies without the liabilities of opioid pain killers he nociceptin opioid receptor NOP the th member of the opioid receptor family and its endogenous peptide ligand nociceptin orphanin FQ N OFQ are emerging new targets for pain medications The NOP receptor and N OFQ are found throughout in pain processing pathways in the brain and spinal cord and modulate opioid function by blocking opioid reward and even tolerance We and others have shown that the natural peptide N OFQ and small molecule NOP agonists and bifunctionalandapos NOP agonists with mu opioid agonist activity show potent analgesic effects on acute and chronic pain are non rewarding and do not develop tolerance These findings suggest that NOP receptor agonists may be an attractive approach to obtain potent analgesic efficacies without opioid related liabilities In our Phase I project we investigated th analgesic potential of NOP agonists in a transgenic mouse model of `sickle cell diseaseandapos SCD which develops spontaneous hyperalgesia similar to the condition in sickle patients SCD is associated with severe pain which remains a major challenge to treat Opioids are the current standard of care but due to side effects and development of tolerance remain a sub optimal approach to treat SCD pain particularly when needed on a continued basis Development of effective analgesics devoid of opioid liabilities would have a significant impact on pain treatment in SCD Our Phase I studies showed that the NOP agonist mu low efficacy agonist AT showed significant antinociceptive efficacy in sickle mice more potent and longer lasting than high dose morphine AT also showed a sustained analgesic effect without tolerance development These promising data that NOP agonists and or NOP mu bifunctional agonists are promising analgesics for treating chronic pain such as sickle pain In this Phase II project we propose to conduct lead optimization and medicinal chemistry to identify novel NOP targeted `preclinical lead candidatesandapos which are optimized for their drug like suitability and novelty hav in vivo efficacy in pain models in rodents and nonhuman primates and preliminary evaluation of toxicity that are ready to be advanced into IND enabling studies for development as pain medications PUBLIC HEALTH RELEVANCE This application proposes early translational studies of lead optimization and efficacy confirmation to develop `preclinical lead candidatesandapos as a novel class of analgesics that have potent opioid like analgesia but without opioid liabilities of constipation tolerance and abuse liability Successful completion of these studies will validate a new approach for the treatment of chronic and severe acute pain and importantly result in preclinical drug candidates that are ready to be advanced into IND enabling studies for development as novel pain medications


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 297.17K | Year: 2013

There are very limited pharmacotherapy options for treatment of alcohol use disorders, with only three drugs currently approved for use. Further, these are only modestly effective and not widely prescribed, possibly due to their lack of efficacy. An Important facet of alcohol addiction that is often under-treated is the possibility of relapse. Effective treatment of alcohol addiction and relapse therefore, requires new, broader pharmacological approaches. Nociceptin/orphanin FQ (N/OFQ), the endogenous peptide agonist of the opioid receptor-like (ORL 1) receptor (also known as NOP) reduces the rewarding actions of ethanol and prevents reinstatement of ethanol seeking in laboratory animals. Importantly, however, N/OFQ is shown to have anti-anxiety-like and anti-stress-like activity, and functions as a CRF antagonist, to reverse behavioral effects of stress in animal models of alcohol addiction. Therefore, NOP receptor agonism appears to be a broad, promising strategy that may be particularly suitable for treating the various aspects of alcohol addiction. The goal of this contract Is to develop potent and selective NOP agonists, specifically optimized for their drug-like suitability, and to assess the effect of a selected optimized NOP agonist on ethanol-inducedconditioned place preference. The outcome of this project will be the identification of efficacious NOP agonist drug candidates, suitable for further development as potential pharmacotherapy for alcohol addiction and relapse prevention. PUBLIC HEALTH RELEVANCE


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 256.89K | Year: 2012

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is associated with severe pain, which remains a major challenge to treat. Opioids are the current standard of care, but due to side effects and development of tolerance and dependence, remain asub-optimal approach to treat SCD pain, particularly when used on a continued basis. Sickle patients therefore live with recurrent difficult-to-treat pain, resulting in frequent hospitalization and loss of productivty. Thus there is a critical need to develop effective therapies devoid of addiction and tolerance to treat severe pain in SCD. We have recently demonstrated that nociceptin receptor (NOP) agonists have significant anti-nociceptive and anti-allodynic effects in an animal model of chronic pain, with efficacies comparable to that of the opioid morphine, in the same model. We further demonstrated that bifunctional NOP/opioid agonists also possess anti-allodynic activity, and do not develop tolerance and have no rewarding effects on their own. The nociceptin receptor NOP and its endogenous ligand nociceptin/orphanin FQ (N/OFQ) are widely distributed in the brain and spinal cord in regions involved in nociceptive responses and are a target for pain therapeutics. The NOP system also modulates opioid effects such as anti-nociception, opioid-induced tolerance and reward. Therefore, from a therapeutic standpoint, NOP receptor agonism appears to be a broad, promising pharmacological strategy to provide pain relief in sickle cell pain, without the liabilitiesassociated with opioid- based therapies, such as constipation, tolerance and dependence. This application therefore proposes proof- of-concept studies to investigate the efficacy of NOP agonists in the treatment of chronic pain associated with sickle celldisease, with the following Specific Aims: Aim 1: To identify one NOP agonist and one bifunctional NOP agonist/mu partial agonist, which have suitable drug-like characteristics and brain penetration, for evaluation in efficacy studies. Aim 2: To determinethe analgesic ability of NOP agonist and NOP agonist/mu partial agonist on pain in sickle mice. We will examine the effect on, (a) tonic hyperalgesia representing chronic pain, (b) acute pain due to vaso-occlusive crises incited by hypoxia/reoxygenation, and (c) inflammation and organ pathology to rule out the adverse effects of NOP-based analgesics. We will use relevant mouse models of sickle cell disease recently developed in our laboratory and employ several different measures of pain including testing for cutaneous and deep tissue hyperalgesia and sensitivity to heat and cold, which will provide comprehensive investigation on different pain characteristics observed clinically in patients with SCD. These studies will facilitate the translation of thepromising efficacy of NOP receptor agonists in chronic pain into therapeutic use to expand the options for pain relief in SCD, without inadvertent opioid-related side effects. Promising, efficacious NOP agonists identified from this project can be furtherdeveloped as potential pharmacotherapy for the treatment of pain in SCD. PUBLIC HEALTH RELEVANCE: Patients with sickle cell disease (SCD) suffer with severe pain throughout life, which is challenging to treat. Opioids are the only therapy widelyused but unfortunately are associated with side effects (constipation) and development of tolerance and addiction. Nociceptin receptor (NOP) agonists are able to produce opioid-level analgesia without the opioid-related side effects, such as tolerance anddependence, in models of pain. If they demonstrate proof-of-efficacy in the animal models of SCD, as proposed in this project, they would offer a tremendous therapeutic advantage to treat pain in SCD without opioid-related side effects.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 999.99K | Year: 2015

Not Available


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 293.35K | Year: 2012

DESCRIPTION (provided by applicant): The overall goal of this SBIR Phase I project is to identify at least two suitable, efficacious preclinical candidates from our novel series of very potent and highly selective 3 4 nicotinic acetylcholine receptor (nAChR) ligands, for further translational development into smoking cessation medications. The promising in vivo efficacy of the highly selective 3 4 nAChR antagonist compound from this series in significant blocking nicotine self-administration in rats, at low doses, with no effect on food responding, strongly supports our hypothesis that ' 3 4 nAChR antagonism' is a promising new pharmacological mechanism for smoking cessation pharmacotherapy, and supports the proposed preclinical ADME assessment and efficacy studies to identify two suitable preclinical candidates from this series for further development. Although there is evidence that success rates for quitting smoking, are 2-3 times higher when pharmacotherapy is used than when no treatments are used, therepertoire of current pharmacotherapies is extremely limited. With the enormous health and economic burdens that smoking has on our society, and notwithstanding the limited efficacy and emerging side-effects of the few currently available smoking cessationmedications, development of new medications for smoking cessation, particularly against new pharmacological targets, is a critical need, to decrease the impact of smoking on health and mortality. Although it is known that the reinforcing and addictive effects of nicotine are due to is actions on the nicotinic acetylcholine receptors, a major barrier in the field has been the identification of the various nAChR subtypes that play a role in the various aspects of nicotine dependence, and their validation asdrug targets. This has been exacerbated by lack of subtype-selective nAChR ligands that can be used as tools or developed as therapeutics. Several recent studies suggest that the 3 4 subtype of the nAChR is important for several aspects of nicotine dependence. Recent genetic association studies show that single nucleotide polymorphisms (SNPs) in the gene cluster CHRNA5/A3/B4, encoding for the 3, 5 and 4 nAChR subunits are associated with increased risk for heavy smoking, inability to quit, and increasedsensitivity to nicotine. Furthermore, the 4 nAChR subunit has been shown to be necessary for nicotine withdrawal. The promising in vivo efficacy of our highly selective 3 4 nAChR antagonist suggests that 3 4 antagonism may be a promising target for smoking cessation and appears to be consistent with the recent genetic studies on the role of the 3 4 subtype. Based on these results, we propose, in this application, a preclinical development program to evaluate this compound series in in vitro ADME studies and in vivo biovailability and blood-brain penetration assays (Aim 1), to select two candidate compounds for full efficacy evaluation in animal models of nicotine self-administration and reinstatement (a model of drug relapse) (Aim 2). Lead optimizationto improve the drug-like suitability of the initial series of compounds is also proposed (Aim 3). Our Specific Aims are designed as a first step toward the preclinical development of this promising class of compounds as pharmacotherapies for tobacco dependence. PUBLIC HEALTH RELEVANCE: The overall goal of the proposed research is to develop our novel 3 4 nAChR antagonists as smoking cessation medications against a new target, the 3 4 nAChRs, which have been recently implicated in several geneticstudies, to be involved in smoking behaviors and withdrawal. Our exciting preliminary data shows that our lead compound dramatically inhibits nicotine self-administration in laboratory animal models. It is our ultimate goal to take this promising series ofcompounds into the clinic, and to provide a new, safe therapeutic option to assist smokers who wish to quit. Successful completion of this project will be the first step in this clinical translation of our promising discoveries, for the development of pharmacotherapies for smoking cessation.


Patent
Astraea Therapeutics, Llc | Date: 2015-01-20

Provided herein are novel and selective high affinity 34 nicotinic acetycholine receptor ligands and pharmaceutical compositions thereof. In other embodiments, provided herein are methods of treatment, prevention, or amelioration of a variety of medical disorders such as, for example, drug addiction or pain using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of selectively antagonizing receptors such as, for example, the 34 nicotinic acetycholine receptor using the compounds and compositions disclosed herein.

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