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Sukhtankar D.D.,University of Michigan | Zaveri N.T.,Astraea Therapeutics, Llc | Husbands S.M.,University of Bath | Ko M.-C.,Wake forest University
Journal of Pharmacology and Experimental Therapeutics | Year: 2013

Nociceptin/orphanin FQ peptide receptor (NOP) agonists produce antinociceptive effects in animal models after spinal administration and potentiate μ-opioid receptor (MOP)-mediated antinociception. This study determined the antinociceptive effects of spinally administered bifunctional NOP/MOP ligands and the antinociceptive functions of spinal NOP and MOP receptors in mice. Antinociceptive effects of bifunctional NOP/MOP ligands BU08028 [(2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3- hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol] and SR16435 [1-(1-(2,3,3α,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl) -indolin-2-one] were pharmacologically compared with the putative bifunctional ligand buprenorphine, selective NOP agonist SCH221510 [3-endo-8-[bis(2- methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol] and selective MOP agonist morphine in neuropathic and inflammatory pain models. Additionally, the degree of tolerance development to the antiallodynic effects of SR16435 and buprenorphine were determined after repeated intrathecal administration. Our data indicated that BU08028 and SR16435 were more potent than morphine and SCH221510 in attenuating nerve injury-induced tactile allodynia and inflammation-induced thermal hyperalgesia. Coadministration of receptor-selective antagonists further revealed that both NOP and MOP in the spinal cord mediated the antiallodynic effects of BU08028 and SR16435, but intrathecal buprenorphine-induced antiallodynic effects were primarily mediated by MOP. Repeated intrathecal administration of SR16435 resulted in reduced and slower development of tolerance to its antiallodynic effects compared with buprenorphine. In conclusion, both NOP and MOP receptors in the spinal cord independently drive anti-nociception in mice. Spinally administered bifunctional NOP/MOP ligands not only can effectively attenuate neuropathic and inflammatory pain, but also have higher antinociceptive potency with reduced tolerance development to analgesia. Such ligands therefore display a promising profile as spinal analgesics. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics. Source

Costello M.R.,University of California at Irvine | Reynaga D.D.,University of California at Irvine | Mojica C.Y.,University of California at Irvine | Zaveri N.T.,Astraea Therapeutics, Llc | And 2 more authors.
Neuropsychopharmacology | Year: 2014

Tobacco dependence is difficult to treat, with the vast majority of those who try to quit relapsing within the first year. Improvements in smoking cessation therapies may be achieved by improving current preclinical research methods. However, most experimental tests in animals use nicotine alone, ignoring the 8000 other constituents found in tobacco smoke. To improve on this model, we have used self-administration to test the reinforcing properties of aqueous cigarette smoke extract (CSE) in rats, made by bubbling cigarette smoke through a saline solution. CSE is more potent than nicotine alone in both the acquisition and maintenance of self-administration, but did not exhibit higher progressive ratio responding. Mecamylamine and varenicline had similar potencies to block nicotine and CSE self-administration, indicating the involvement of nicotinic receptors in CSE reinforcement. Following extinction of responding, reinstatement was triggered by exposing animals to a pharmacological stressor, yohimbine (2.5 mg/kg, i.p.), alone and in combination with cues. Animals that self-administered CSE were significantly more sensitive to stress-induced reinstatement than those that self-administered nicotine. Ligand binding autoradiography studies showed nicotine and CSE to have similar affinities for different nicotinic receptor types. CSE significantly reduced MAO-A and MAO-B activities in vitro, whereas nicotine did not. Although CSE inhibition of MAO-A activity in vitro was found to be partially irreversible, irreversible inhibition was not observed in vivo. These experiments show that CSE is an effective reinforcer acting via nicotinic receptors. Furthermore, it better models MAO inhibition and is more sensitive to stress-induced reinstatement than nicotine alone, which is a potent trigger for relapse in smokers. © 2014 American College of Neuropsychopharmacology. All rights reserved. Source

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

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

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.

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