Kappa Antagonists

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Philip S. Portoghese - One of the best experts on this subject based on the ideXlab platform.

  • Molecular recognition at Kappa opioid receptors
    Pure and Applied Chemistry, 2001
    Co-Authors: Philip S. Portoghese
    Abstract:

    Structure-activity relationships are rarely straightforward, and often are more com- plicated than they appear. For this reason, the use of site-directed mutagenesis as a comple- mentary tool to analyze structure-activity relationships has been invaluable. Here, we illus- trate how site-directed mutagenesis has led to greater insight into the molecular basis for molecular recognition of norbinaltorphimine and to the design of novel Kappa Antagonists. Given the paucity of high-resolution crystal structures for membrane-bound receptors, the use of a coordinated "two-dimensional" paradigm that involves molecular modification of both the ligand and the receptor, affords a useful approach to the study of molecular recog- nition. This paradigm has led to the design of highly potent and selective Kappa opioid recep- tor Antagonists that are derivatives of the delta opioid receptor antagonist, naltrindole.

  • Binding of norbinaltorphimine (norBNI) congeners to wild-type and mutant mu and Kappa opioid receptors: molecular recognition loci for the pharmacophore and address components of Kappa Antagonists.
    Journal of medicinal chemistry, 2000
    Co-Authors: Dennis L. Larson, Robert M. Jones, Siv A. Hjorth, Thue W. Schwartz, Philip S. Portoghese
    Abstract:

    Molecular modifications of both the Kappa opioid antagonist norbinaltorphimine (norBNI, 1) and the Kappa receptor have provided evidence that the selectivity of this ligand is conferred through ionic interaction if its N17‘ protonated amine group (an “address”) with a nonconserved acidic residue (Glu297) on the Kappa receptor. In the present study, we have examined the effect of structural modifications on the affinity of norBNI analogues for wild-type and mutant Kappa and mu opioid receptors expressed in COS-7 cells. Compounds 2, 3, and 7, which have an antagonist pharmacophore and basic N17‘ group in common with norBNI, retained high affinity for the wild-type Kappa but exhibited greatly reduced affinity for mutant Kappa receptors (E297K and E297A). Modification of the phenolic or N-substituent groups of the antagonist pharmacophore (4 and 5) or removal of basicity at the address N17‘ center (6) led to greatly reduced affinity for the wild-type and mutant receptors. The reduced affinity upon modificatio...

  • Structure-activity relationship of N17'-substituted norbinaltorphimine congeners. Role of the N17' basic group in the interaction with a putative address subsite on the Kappa opioid receptor.
    Journal of medicinal chemistry, 1994
    Co-Authors: Philip S. Portoghese, C. E. Lin, F. Farouz-grant, A. E. Takemori
    Abstract:

    A series of norbinaltorphimine congeners (2-12) which contain different groups at the N17'-position have been synthesized in order to evaluate the role of N17' in conferring Kappa opioid antagonist selectivity at opioid receptor sites. The compounds that contain a basic N17' nitrogen (2-9) were found to be selective Kappa Antagonists. Amidation of N17' afforded congeners 10-12 with feeble Kappa antagonist potency and low selectivity. The fact that potent antagonism and selectivity were observed only when members of the series contain a basic N17' nitrogen suggests that it interacts with extracellular domains of the Kappa receptor that contain acidic amino acid residues. The N-terminal domain and extracellular loop 2, both of which contain acidic residues, are candidates for this interaction and may be components of the Kappa address subsite of the receptor.

Stephen M. Husbands - One of the best experts on this subject based on the ideXlab platform.

  • The antidepressant-like effects of BU10119, a novel Kappa opioid receptor antagonist, in the novelty-induced hypophagia task in mice
    Social Neuroscience, 2015
    Co-Authors: Sarah J. Bailey, Abdulrahman Mohammed I Almatroudi, Christopher Bailey, Stephen M. Husbands
    Abstract:

    Antagonists at Kappa-opioid receptors have been proposed as novel antidepressants. The standard high-affinity, selective Kappa-Antagonists have a long lasting duration of action which potentially limits their use (Carroll and Carlezon 2013. J Med Chem 56: 2178-2195). We have previously shown that the combination of buprenorphine (1mg/kg) with naltrexone (1mg/kg) produced a functional short-acting Kappa-antagonist, that was non-sedating and non-rewarding, with antidepressant like effects in the forced swim test and novelty-induced hypophagia task (Almatroudi et al. 2015. J. Psychopharmacol. In Press). We have developed a novel compound that combines the properties of buprenorphine/naltrexone combination into a single compound (Cueva et al. 2015. J Med Chem, In Press), thereby simplifying dosing and treatment regimens and avoiding abuse potential. Here, we present preliminary data that BU10119 is a functional Kappa antagonist with antidepressant-like effects in mice. Adult male CD-1 mice (8-9 weeks) were used. For novelty-induced hypophagia, mice were individually housed and trained for 3 days to consume condensed milk. On test days, mice were injected intraperitoneally (10 ml/kg) with saline, buprenorphine/naltrexone combination (1 mg/kg), fluoxetine (20 mg/kg) or BU10119 (1mg/kg) one hour prior to testing behaviour. The latency to drink and consumption were recorded in the home cage (day 4) and in the novel cage (day5). One-way ANOVA, revealed that there was a significant effect of drug treatment on the latency to drink in the novel cage (F (4, 45) =9.15, P

  • The antidepressant-like effects of combination buprenorphine/naltrexone in the novelty-induced hypophagia task in mice
    Social Neuroscience, 2014
    Co-Authors: Sarah J. Bailey, Abdulrahman Mohammed I Almatroudi, Christopher Bailey, Stephen M. Husbands
    Abstract:

    Antagonists at Kappa-opioid receptors have been proposed as novel antidepressants. The standard high-affinity, selective Kappa-Antagonists have a long lasting duration of action which potentially limits their use (Carroll and Carlezon 2013. J Med Chem 56: 2178-2195). Buprenorphine is a partial mu-opioid receptor agonist and a Kappa-antagonist, while naltrexone is a non-selective opioid antagonist. We have previously shown that the combination of buprenorphine (1mg/kg) with naltrexone (1mg/kg) produced a functional short-acting Kappa-antagonist that was non-sedating and non-rewarding in mice. Here, we report the effects of this combination treatment on depression-related behaviour. Adult male CD-1 mice (8-9 weeks) were used. For novelty-induced hypophagia, mice were individually housed and trained for 3 days to consume condensed milk. On test days, mice were injected intraperitoneally (10 ml/kg) with saline, buprenorphine alone (1 mg/kg), naltrexone alone (1 mg/kg), buprenorphine/naltrexone combination (1 mg/kg), norBNI (10mg/kg) or fluoxetine (20 mg/kg) one hour prior to testing behaviour. The latency to drink and consumption were recorded in the home cage (day 4) and in the novel cage (day5). One-way ANOVA, revealed that there was a significant effect of drug treatment on the latency to drink in the novel cage (F (5, 54) =8.5, P

Sarah J. Bailey - One of the best experts on this subject based on the ideXlab platform.

  • The antidepressant-like effects of BU10119, a novel Kappa opioid receptor antagonist, in the novelty-induced hypophagia task in mice
    Social Neuroscience, 2015
    Co-Authors: Sarah J. Bailey, Abdulrahman Mohammed I Almatroudi, Christopher Bailey, Stephen M. Husbands
    Abstract:

    Antagonists at Kappa-opioid receptors have been proposed as novel antidepressants. The standard high-affinity, selective Kappa-Antagonists have a long lasting duration of action which potentially limits their use (Carroll and Carlezon 2013. J Med Chem 56: 2178-2195). We have previously shown that the combination of buprenorphine (1mg/kg) with naltrexone (1mg/kg) produced a functional short-acting Kappa-antagonist, that was non-sedating and non-rewarding, with antidepressant like effects in the forced swim test and novelty-induced hypophagia task (Almatroudi et al. 2015. J. Psychopharmacol. In Press). We have developed a novel compound that combines the properties of buprenorphine/naltrexone combination into a single compound (Cueva et al. 2015. J Med Chem, In Press), thereby simplifying dosing and treatment regimens and avoiding abuse potential. Here, we present preliminary data that BU10119 is a functional Kappa antagonist with antidepressant-like effects in mice. Adult male CD-1 mice (8-9 weeks) were used. For novelty-induced hypophagia, mice were individually housed and trained for 3 days to consume condensed milk. On test days, mice were injected intraperitoneally (10 ml/kg) with saline, buprenorphine/naltrexone combination (1 mg/kg), fluoxetine (20 mg/kg) or BU10119 (1mg/kg) one hour prior to testing behaviour. The latency to drink and consumption were recorded in the home cage (day 4) and in the novel cage (day5). One-way ANOVA, revealed that there was a significant effect of drug treatment on the latency to drink in the novel cage (F (4, 45) =9.15, P

  • The antidepressant-like effects of combination buprenorphine/naltrexone in the novelty-induced hypophagia task in mice
    Social Neuroscience, 2014
    Co-Authors: Sarah J. Bailey, Abdulrahman Mohammed I Almatroudi, Christopher Bailey, Stephen M. Husbands
    Abstract:

    Antagonists at Kappa-opioid receptors have been proposed as novel antidepressants. The standard high-affinity, selective Kappa-Antagonists have a long lasting duration of action which potentially limits their use (Carroll and Carlezon 2013. J Med Chem 56: 2178-2195). Buprenorphine is a partial mu-opioid receptor agonist and a Kappa-antagonist, while naltrexone is a non-selective opioid antagonist. We have previously shown that the combination of buprenorphine (1mg/kg) with naltrexone (1mg/kg) produced a functional short-acting Kappa-antagonist that was non-sedating and non-rewarding in mice. Here, we report the effects of this combination treatment on depression-related behaviour. Adult male CD-1 mice (8-9 weeks) were used. For novelty-induced hypophagia, mice were individually housed and trained for 3 days to consume condensed milk. On test days, mice were injected intraperitoneally (10 ml/kg) with saline, buprenorphine alone (1 mg/kg), naltrexone alone (1 mg/kg), buprenorphine/naltrexone combination (1 mg/kg), norBNI (10mg/kg) or fluoxetine (20 mg/kg) one hour prior to testing behaviour. The latency to drink and consumption were recorded in the home cage (day 4) and in the novel cage (day5). One-way ANOVA, revealed that there was a significant effect of drug treatment on the latency to drink in the novel cage (F (5, 54) =8.5, P

Kenner C. Rice - One of the best experts on this subject based on the ideXlab platform.

  • Effects of Kappa opioids in an assay of pain-depressed intracranial self-stimulation in rats
    Psychopharmacology, 2010
    Co-Authors: S. Stevens Negus, Ember M. Morrissey, Kejun Cheng, Marisa Rosenberg, Kenner C. Rice
    Abstract:

    Rationale Selective, centrally acting Kappa opioid agonists produce antinociception in a wide range of preclinical assays, but these compounds perform poorly as analgesics in humans. This discrepancy may be related to the behavioral depressant effects of Kappa agonists. Kappa Antagonists do not typically produce antinociception, but they produce antidepressant-like effects in some preclinical assays . Objective The objective of this study was to test the hypothesis that the Kappa agonist U69,593 and the Kappa antagonist norbinaltorphimine would produce pronociceptive and antinociceptive effects, respectively, in an assay of pain-depressed behavior. Methods Effects of U69,593 (0.056–0.56 mg/kg), norbinaltorphimine (10–32 mg/kg), and morphine (3.2 mg/kg) were evaluated on the stimulation of a stretching response and the depression of intracranial self-stimulation (ICSS) of the medial forebrain bundle produced in rats by a common noxious stimulus (intraperitoneal administration of dilute lactic acid). Results U69,593 produced a dose-dependent blockade of acid-stimulated stretching but only exacerbated acid-induced depression of ICSS. Thus, U69,593 produced antinociception in the assay of pain-stimulated behavior but pronociceptive effects in the assay of pain-depressed behavior. Norbinaltorphimine did not alter acid-stimulated stretching or acid-induced depression of ICSS. The mu opioid agonist morphine blocked both acid-stimulated stretching and acid-induced depression of ICSS. Conclusions These results support the hypothesis that prodepressant effects of Kappa agonists may limit their clinical utility as analgesics. These results do not support the use of Kappa Antagonists to treat depressant effects of pain. These findings illustrate the potential value of using complementary assays of pain-stimulated and pain-depressed behaviors for preclinical evaluation of candidate analgesics.

  • Effects of Kappa opioids in an assay of pain-depressed intracranial self-stimulation in rats
    Psychopharmacology, 2010
    Co-Authors: S. Stevens Negus, Ember M. Morrissey, Kejun Cheng, Marisa Rosenberg, Kenner C. Rice
    Abstract:

    Rationale Selective, centrally acting Kappa opioid agonists produce antinociception in a wide range of preclinical assays, but these compounds perform poorly as analgesics in humans. This discrepancy may be related to the behavioral depressant effects of Kappa agonists. Kappa Antagonists do not typically produce antinociception, but they produce antidepressant-like effects in some preclinical assays . Objective The objective of this study was to test the hypothesis that the Kappa agonist U69,593 and the Kappa antagonist norbinaltorphimine would produce pronociceptive and antinociceptive effects, respectively, in an assay of pain-depressed behavior. Methods Effects of U69,593 (0.056–0.56 mg/kg), norbinaltorphimine (10–32 mg/kg), and morphine (3.2 mg/kg) were evaluated on the stimulation of a stretching response and the depression of intracranial self-stimulation (ICSS) of the medial forebrain bundle produced in rats by a common noxious stimulus (intraperitoneal administration of dilute lactic acid). Results U69,593 produced a dose-dependent blockade of acid-stimulated stretching but only exacerbated acid-induced depression of ICSS. Thus, U69,593 produced antinociception in the assay of pain-stimulated behavior but pronociceptive effects in the assay of pain-depressed behavior. Norbinaltorphimine did not alter acid-stimulated stretching or acid-induced depression of ICSS. The mu opioid agonist morphine blocked both acid-stimulated stretching and acid-induced depression of ICSS. Conclusions These results support the hypothesis that prodepressant effects of Kappa agonists may limit their clinical utility as analgesics. These results do not support the use of Kappa Antagonists to treat depressant effects of pain. These findings illustrate the potential value of using complementary assays of pain-stimulated and pain-depressed behaviors for preclinical evaluation of candidate analgesics.

  • Effects of Kappa opioids in an assay of pain-depressed intracranial self-stimulation in rats.
    Psychopharmacology, 2010
    Co-Authors: S. Stevens Negus, Ember M. Morrissey, Marisa B. Rosenberg, Kejun Cheng, Kenner C. Rice
    Abstract:

    Rationale Selective, centrally acting Kappa opioid agonists produce antinociception in a wide range of preclinical assays, but these compounds perform poorly as analgesics in humans. This discrepancy may be related to the behavioral depressant effects of Kappa agonists. Kappa Antagonists do not typically produce antinociception, but they produce antidepressant-like effects in some preclinical assays.

Christopher Bailey - One of the best experts on this subject based on the ideXlab platform.

  • The antidepressant-like effects of BU10119, a novel Kappa opioid receptor antagonist, in the novelty-induced hypophagia task in mice
    Social Neuroscience, 2015
    Co-Authors: Sarah J. Bailey, Abdulrahman Mohammed I Almatroudi, Christopher Bailey, Stephen M. Husbands
    Abstract:

    Antagonists at Kappa-opioid receptors have been proposed as novel antidepressants. The standard high-affinity, selective Kappa-Antagonists have a long lasting duration of action which potentially limits their use (Carroll and Carlezon 2013. J Med Chem 56: 2178-2195). We have previously shown that the combination of buprenorphine (1mg/kg) with naltrexone (1mg/kg) produced a functional short-acting Kappa-antagonist, that was non-sedating and non-rewarding, with antidepressant like effects in the forced swim test and novelty-induced hypophagia task (Almatroudi et al. 2015. J. Psychopharmacol. In Press). We have developed a novel compound that combines the properties of buprenorphine/naltrexone combination into a single compound (Cueva et al. 2015. J Med Chem, In Press), thereby simplifying dosing and treatment regimens and avoiding abuse potential. Here, we present preliminary data that BU10119 is a functional Kappa antagonist with antidepressant-like effects in mice. Adult male CD-1 mice (8-9 weeks) were used. For novelty-induced hypophagia, mice were individually housed and trained for 3 days to consume condensed milk. On test days, mice were injected intraperitoneally (10 ml/kg) with saline, buprenorphine/naltrexone combination (1 mg/kg), fluoxetine (20 mg/kg) or BU10119 (1mg/kg) one hour prior to testing behaviour. The latency to drink and consumption were recorded in the home cage (day 4) and in the novel cage (day5). One-way ANOVA, revealed that there was a significant effect of drug treatment on the latency to drink in the novel cage (F (4, 45) =9.15, P

  • The antidepressant-like effects of combination buprenorphine/naltrexone in the novelty-induced hypophagia task in mice
    Social Neuroscience, 2014
    Co-Authors: Sarah J. Bailey, Abdulrahman Mohammed I Almatroudi, Christopher Bailey, Stephen M. Husbands
    Abstract:

    Antagonists at Kappa-opioid receptors have been proposed as novel antidepressants. The standard high-affinity, selective Kappa-Antagonists have a long lasting duration of action which potentially limits their use (Carroll and Carlezon 2013. J Med Chem 56: 2178-2195). Buprenorphine is a partial mu-opioid receptor agonist and a Kappa-antagonist, while naltrexone is a non-selective opioid antagonist. We have previously shown that the combination of buprenorphine (1mg/kg) with naltrexone (1mg/kg) produced a functional short-acting Kappa-antagonist that was non-sedating and non-rewarding in mice. Here, we report the effects of this combination treatment on depression-related behaviour. Adult male CD-1 mice (8-9 weeks) were used. For novelty-induced hypophagia, mice were individually housed and trained for 3 days to consume condensed milk. On test days, mice were injected intraperitoneally (10 ml/kg) with saline, buprenorphine alone (1 mg/kg), naltrexone alone (1 mg/kg), buprenorphine/naltrexone combination (1 mg/kg), norBNI (10mg/kg) or fluoxetine (20 mg/kg) one hour prior to testing behaviour. The latency to drink and consumption were recorded in the home cage (day 4) and in the novel cage (day5). One-way ANOVA, revealed that there was a significant effect of drug treatment on the latency to drink in the novel cage (F (5, 54) =8.5, P