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Gary Astonjones - One of the best experts on this subject based on the ideXlab platform.

  • the Orexin 1 Receptor antagonist sb 334867 reduces motivation but not inhibitory control in a rat stop signal task
    Brain Research, 2020
    Co-Authors: Joost Wiskerke, Morgan H. James, Gary Astonjones
    Abstract:

    There is considerable clinical interest in the neuropeptide Orexin/hypocretin for its ability to regulate motivation and reward as well as arousal and wakefulness. For instance, antagonists for the Orexin-1 Receptor (OxR1) are thought to hold great promise for treating drug addiction and disorders associated with overeating, as these compounds repeatedly have been found to suppress seeking of various drugs of abuse as well as highly palatable foods in preclinical models. Given the hypothesized role of OxR1 signaling in cue-driven motivation, an outstanding question is whether pharmacologically blocking this Receptor affects cognitive functioning. Response inhibition - the ability to cancel ongoing behavior - is one aspect of cognitive control that may be particularly relevant. Response inhibition deficits are commonly associated with a range of psychiatric disorders and neurological diseases, including substance use disorders and obesity. Moreover, OxR1 signaling recently has been implicated in waiting impulsivity, another aspect of inhibitory control. Here, we investigated the effects of the OxR1 antagonist SB-334867 on response inhibition in a rat version of the stop-signal reaction time task. Results show that acutely blocking OxR1 had minimal effects on response inhibition or attentional functioning. In contrast, this manipulation reduced motivation to perform the task and earn food rewards, consistent with other recent findings. These results add to the growing body of literature implicating OxR1 in the regulation of motivation and suggest that effects of pharmacological compounds such as SB-334867 on drug-seeking behavior are not related to effects on response inhibition.

  • persistent effects of the Orexin 1 Receptor antagonist sb 334867 on motivation for the fast acting opioid remifentanil
    Brain Research, 2020
    Co-Authors: Caroline B. Pantazis, Aida Mohammadkhani, Morgan H. James, Gary Astonjones
    Abstract:

    Abstract The Orexin (hypocretin) system is multifaceted, and regulates sleep-wake cycles, nociception, endocrine function and reward-seeking behavior. We have established an important role for this system in motivation for drugs of abuse. The Orexin-1 Receptor (Ox1R) antagonist SB334867 (SB) reduces seeking of drug reward under conditions of high motivation. There is some evidence that the effects of systemic SB on reward seeking persist beyond the pharmacological availability of the drug, however the time course of these effects is not well characterized, nor is it known whether similar persistent effects are observed following intraparenchymal injections. Here, we used a behavioral economics paradigm, which allows for repeated testing of drug motivation across consecutive days, to examine the persistent effects of acute systemic and local treatment with SB on motivation for the short-acting μ‐opioid Receptor agonist remifentanil. Systemic injections of SB immediately prior to behavioral testing reduced motivation for remifentanil; this effect was sustained on a subsequent test at 24 h, but not on a third test at 48 h. When injected into ventral pallidum (VP) the effects of SB were more persistent, with reduced motivation observed for up to 48 h. We next made SB injections into VP 24 h prior to behavioral testing; this produced effects that persisted for at least 72 h post-treatment. Cued reinstatement of extinguished remifentanil seeking was also attenuated by pretreatment with SB 24 h earlier. These data indicate that the effects of SB on opioid seeking behavior persist beyond the bioavailability of the compound. These observations have important ramifications for the future clinical use of Orexin Receptor antagonists for the treatment of addiction.

  • persistent effects of the Orexin 1 Receptor antagonist sb 334867 on motivation for the fast acting opioid remifentanil
    bioRxiv, 2019
    Co-Authors: Aida Mohammadkhani, Morgan H. James, Gary Astonjones
    Abstract:

    The Orexin (hypocretin) system is important for reward-seeking behavior. The Orexin-1 Receptor (Ox1R) antagonist SB334867 (SB) reduces seeking of food and drug reward under conditions of high motivation. There is some evidence that the effects of systemic SB on reward seeking persist beyond the pharmacological availability of the drug, however the time course of these effects is not well characterized, nor is it known whether similar persistent effects are observed following intraparenchymal injections. Here, we used a behavioral economics paradigm, which allows for repeated testing of drug motivation across consecutive days, to examine the persistent effects of acute systemic and local treatment with SB on motivation for the short-acting opioid remifentanil. Systemic injections of SB immediately prior to behavioral testing reduced motivation for remifentanil; this effect was sustained on a subsequent test at 24h, but not on a third test at 48h. When injected locally into caudal ventral pallidum (cVP) the effects of SB were more persistent, with reduced motivation observed for up to 48h. We next made SB injections into cVP 24h prior to behavioral testing; this produced persistent effects that persisted for at least 72h post-treatment. Cued reinstatement of extinguished remifentanil seeking was also attenuated by pretreatment with SB 24h prior. These data indicate that the effects of SB on opioid seeking behavior persist beyond the bioavailability of the compound. These observations might have important ramifications for the future clinical use of Orexin Receptor antagonists for the treatment of addiction.

  • the Orexin 1 Receptor antagonist sb 334867 reduces motivation but not inhibitory control in a rat stop signal task
    bioRxiv, 2018
    Co-Authors: Joost Wiskerke, Morgan H. James, Gary Astonjones
    Abstract:

    There is considerable clinical interest in the neuropeptide Orexin/hypocretin for its ability to regulate motivation and reward as well as arousal and wakefulness. For instance, antagonists for the Orexin-1 Receptor (OxR1) are thought to hold great promise for treating drug addiction and disorders associated with overeating, as these compounds repeatedly have been found to suppress seeking of various drugs of abuse as well as highly palatable foods in preclinical models. Given the hypothesized role of OxR1 signaling in cue-driven motivation, an outstanding question is whether pharmacologically blocking this Receptor affects cognitive functioning. Response inhibition - the ability to cancel ongoing behavior - is one aspect of cognitive control that may be particularly relevant. Response inhibition deficits are commonly associated with a range of psychiatric disorders and neurological diseases, including substance use disorders and obesity. Moreover, OxR1 signaling recently has been implicated in waiting impulsivity, another aspect of inhibitory control. Here, we investigated the effects of the OxR1 antagonist SB-334867 on response inhibition in a rat version of the stop signal reaction time task. Results show that acutely blocking OxR1 had minimal effects on response inhibition or attentional functioning. In contrast, this manipulation reduced motivation to perform the task and earn food rewards. These results add to the growing body of literature implicating OxR1 in the regulation of motivation and suggest that effects of pharmacological compounds such as SB-334867 on drug seeking behavior are not related to effects on response inhibition.

  • Orexin 1 Receptor signaling increases motivation for cocaine associated cues
    European Journal of Neuroscience, 2015
    Co-Authors: Brandon S. Bentzley, Gary Astonjones
    Abstract:

    The Orexin/hypocretin system is involved in multiple cocaine addiction processes that involve drug-associated environmental cues, including cue-induced reinstatement of extinguished cocaine seeking and expression of conditioned place preference. However, the Orexin system does not play a role in several behaviors that are less cue-dependent, such as cocaine-primed reinstatement of extinguished cocaine seeking and low-effort cocaine self-administration. We hypothesized that cocaine-associated cues, but not cocaine alone, engage signaling at Orexin-1 Receptors (OX1R), and this cue-engaged OX1R signaling increases motivation for cocaine. Motivation for cocaine was measured in Sprague-Dawley rats with behavioral-economic demand curve analysis after pretreatment with the OX1R antagonist SB-334867 (SB) or vehicle with and without light+tone cues. Demand for cocaine was higher when cocaine-associated cues were present, and SB only reduced cocaine demand in the presence of these cues. We then asked if cocaine demand is linked to cued-reinstatement of cocaine seeking, as both procedures are partially driven by cocaine-associated cues in an Orexin-dependent manner. SB blocked cue-induced reinstatement behavior, and baseline demand predicted SB efficacy with the largest effect in high demand animals, i.e., animals with the greatest cue-dependent behavior. We conclude that OX1R signaling increases the reinforcing efficacy of cocaine-associated cues but not for cocaine alone. This supports our view that Orexin plays a prominent role in the ability of conditioned cues to activate motivational responses.

Morgan H. James - One of the best experts on this subject based on the ideXlab platform.

  • persistent effects of the Orexin 1 Receptor antagonist sb 334867 on motivation for the fast acting opioid remifentanil
    Brain Research, 2020
    Co-Authors: Caroline B. Pantazis, Aida Mohammadkhani, Morgan H. James, Gary Astonjones
    Abstract:

    Abstract The Orexin (hypocretin) system is multifaceted, and regulates sleep-wake cycles, nociception, endocrine function and reward-seeking behavior. We have established an important role for this system in motivation for drugs of abuse. The Orexin-1 Receptor (Ox1R) antagonist SB334867 (SB) reduces seeking of drug reward under conditions of high motivation. There is some evidence that the effects of systemic SB on reward seeking persist beyond the pharmacological availability of the drug, however the time course of these effects is not well characterized, nor is it known whether similar persistent effects are observed following intraparenchymal injections. Here, we used a behavioral economics paradigm, which allows for repeated testing of drug motivation across consecutive days, to examine the persistent effects of acute systemic and local treatment with SB on motivation for the short-acting μ‐opioid Receptor agonist remifentanil. Systemic injections of SB immediately prior to behavioral testing reduced motivation for remifentanil; this effect was sustained on a subsequent test at 24 h, but not on a third test at 48 h. When injected into ventral pallidum (VP) the effects of SB were more persistent, with reduced motivation observed for up to 48 h. We next made SB injections into VP 24 h prior to behavioral testing; this produced effects that persisted for at least 72 h post-treatment. Cued reinstatement of extinguished remifentanil seeking was also attenuated by pretreatment with SB 24 h earlier. These data indicate that the effects of SB on opioid seeking behavior persist beyond the bioavailability of the compound. These observations have important ramifications for the future clinical use of Orexin Receptor antagonists for the treatment of addiction.

  • the Orexin 1 Receptor antagonist sb 334867 reduces motivation but not inhibitory control in a rat stop signal task
    Brain Research, 2020
    Co-Authors: Joost Wiskerke, Morgan H. James, Gary Astonjones
    Abstract:

    There is considerable clinical interest in the neuropeptide Orexin/hypocretin for its ability to regulate motivation and reward as well as arousal and wakefulness. For instance, antagonists for the Orexin-1 Receptor (OxR1) are thought to hold great promise for treating drug addiction and disorders associated with overeating, as these compounds repeatedly have been found to suppress seeking of various drugs of abuse as well as highly palatable foods in preclinical models. Given the hypothesized role of OxR1 signaling in cue-driven motivation, an outstanding question is whether pharmacologically blocking this Receptor affects cognitive functioning. Response inhibition - the ability to cancel ongoing behavior - is one aspect of cognitive control that may be particularly relevant. Response inhibition deficits are commonly associated with a range of psychiatric disorders and neurological diseases, including substance use disorders and obesity. Moreover, OxR1 signaling recently has been implicated in waiting impulsivity, another aspect of inhibitory control. Here, we investigated the effects of the OxR1 antagonist SB-334867 on response inhibition in a rat version of the stop-signal reaction time task. Results show that acutely blocking OxR1 had minimal effects on response inhibition or attentional functioning. In contrast, this manipulation reduced motivation to perform the task and earn food rewards, consistent with other recent findings. These results add to the growing body of literature implicating OxR1 in the regulation of motivation and suggest that effects of pharmacological compounds such as SB-334867 on drug-seeking behavior are not related to effects on response inhibition.

  • Orexin-1 Receptor Signaling in Ventral Pallidum Regulates Motivation for the Opioid Remifentanil.
    The Journal of neuroscience : the official journal of the Society for Neuroscience, 2019
    Co-Authors: Aida Mohammadkhani, Jennifer E. Fragale, Caroline B. Pantazis, Hannah E. Bowrey, Morgan H. James, Gary Aston-jones
    Abstract:

    Signaling at the Orexin-1 Receptor (OxR1) is important for motivated drug taking. Using a within-session behavioral economics (BE) procedure, we previously found that pharmacologic blockade of the OxR1 decreased motivation (increased demand elasticity) for the potent and short-acting opioid remifentanil and reduced low-effort remifentanil consumption. However, the mechanism through which Orexin regulates remifentanil demand is currently unknown. Previous work implicated OxR1 signaling within ventral pallidum (VP) as a potential target. VP is densely innervated by Orexin fibers and is known to regulate opioid reward. Accordingly, this study sought to determine the role of VP OxR1 signaling in remifentanil demand and cue-induced reinstatement of remifentanil seeking in male rats. Intra-VP microinjections of the OxR1 antagonist SB-334867 (SB) decreased motivation (increased demand elasticity; α) for remifentanil without affecting remifentanil consumption at low effort. Baseline α values predicted the degree of cue-induced remifentanil seeking, and microinjection of SB into VP attenuated this behavior without affecting extinction responding. Baseline α values also predicted SB efficacy, such that SB was most effective in attenuating reinstatement behavior in highly motivated rats. Together, these findings support a selective role for VP OxR1 signaling in motivation for the opioid remifentanil. Our findings also highlight the utility of BE in predicting relapse propensity and efficacy of treatment with OxR1 antagonists. SIGNIFICANCE STATEMENT Abuse of opioids has risen rapidly and continues to be a major health crisis. Thus, there is an urgent need to better understand the neurobiological and behavioral mechanisms underlying opioid addiction. Here, we investigate the role of Orexin-1 Receptor signaling (OxR1) within ventral pallidum (VP) in remifentanil demand and cue-induced reinstatement of remifentanil seeking. Using a within-session behavioral economics procedure, we show that intra-VP microinjections of the OxR1 antagonist SB-334867 decreased motivation (increased demand elasticity) without affecting remifentanil consumption at low effort. We also found that SB microinjected intra-VP attenuated cue-induced reinstatement of remifentanil seeking. Together, our results support a role for VP OxR1 signaling in opioid reward.

  • The role of Orexin-1 Receptor signaling in demand for the opioid fentanyl
    Neuropsychopharmacology, 2019
    Co-Authors: Jennifer E. Fragale, Caroline B. Pantazis, Morgan H. James, Gary Aston-jones
    Abstract:

    The Orexin system is a potential treatment target for drug addiction. Orexin-1 Receptor (OxR1) antagonism reduces demand for cocaine and remifentanil, indicating that Orexin-based therapies may reduce demand for many classes of abused drugs. However, pharmacokinetics vary greatly among opioids and it is unclear if OxR1 antagonism would reduce demand for all opioids, particularly ones with high abuse liability. Here, we established a behavioral economics (BE) procedure to assess the effects of OxR1 antagonism on demand for the highly abused opioid fentanyl. We also investigated the utility of our procedure to predict OxR1 antagonism efficacy and relapse propensity. Demand parameters α (demand elasticity or price sensitivity of consumption, an inverse measure of drug motivation) and Q _o (drug consumption at null cost) were assessed. The OxR1 antagonist SB-334867 (SB) decreased motivation (increased α ) for fentanyl without affecting Q _o. Baseline α values predicted SB efficacy, such that SB was most effective at reducing motivation (increasing α ) in highly motivated rats. Baseline α values predicted the amount of cued reinstatement of fentanyl seeking; this reinstatement behavior was attenuated by SB administration. These results highlight the promise of the Orexin system as a treatment target for opioid addiction and emphasize the usefulness of BE procedures in the study of opioid abuse.

  • The Role of Orexin-1 Receptor Signaling in Demand for the Opioid Fentanyl
    2019
    Co-Authors: Jennifer E. Fragale, Caroline B. Pantazis, Morgan H. James, Gary Aston-jones
    Abstract:

    The Orexin system is a potential treatment target for drug addiction. Orexin-1 Receptor (OxR1) antagonism reduces demand for cocaine and remifentanil indicating that Orexin-based therapies may reduce demand for many classes of abused drugs. However, pharmacokinetics vary greatly among opioids and it is unclear if OxR1 antagonism would reduce demand for all opioids, particularly ones with particularly high abuse liability. Here, we establish a behavioral economics (BE) procedure to assess the effects of OxR1 antagonism on demand for the highly abused opioid fentanyl. We also investigate the utility of our novel procedure in predicting OxR1 antagonism efficacy and relapse propensity. The OxR1 antagonist SB-334867 (SB) increased demand elasticity (increased alpha, decreased motivation) for fentanyl without affecting preferred consumption of fentanyl at null cost (Qo). Baseline alpha values predicted SB efficacy, such that SB was most effective at increasing demand elasticity in highly motivated rats. SB also attenuated cue-induced fentanyl seeking and baseline alpha values predicted the amount of reinstatement behavior. These results highlight the promise of the Orexin system as a treatment target for opioid addiction and emphasize the usefulness of BE procedures in the study of opioid abuse.

Yukiko Ishikawa - One of the best experts on this subject based on the ideXlab platform.

  • essential structure of Orexin 1 Receptor antagonist ynt 707 part v structure activity relationship study of the substituents on the 17 amino group
    Bioorganic & Medicinal Chemistry Letters, 2020
    Co-Authors: Tsuyoshi Saitoh, Yoko Irukayamatomobe, Noriki Kutsumura, Naoshi Yamamoto, Yasuyuki Nagumo, Kazunori Seki, Ryo Nakajima, Yasuhiro Ogawa, Yukiko Ishikawa, Masashi Yanagisawa
    Abstract:

    Abstract The morphinan-type Orexin 1 Receptor (OX1R) antagonists such as YNT-707 (2) and YNT-1310 (3) show potent and extremely high selective antagonistic activity against OX1R. In the course of our studies of the essential structure of 2, we identified new scaffolds by simplification of the morphinan skeleton. However, the new chemical entities carrying the D-ring removed scaffold showed insufficient activity. To improve the activity of these derivatives, we investigated the effect of substituents mainly focused on the 17-nitrogen group. The 17-N-substituted derivatives, as well as the cyclic derivatives, were synthesized and examined the OX1R antagonistic activity. The assay results showed the interesting relationship between the OX1R antagonistic activity and the substituents on the 17-nitrogen: the antagonistic activity was increased as the bulkiness of 17-substituents increased. Finally, the 17-N-Boc derivative 14a showed the most potent OX1R antagonistic activity (Ki = 14.8 nM).

  • essential structure of Orexin 1 Receptor antagonist ynt 707 part iv the role of d ring in 4 5 epoxymorphinan on the Orexin 1 Receptor antagonistic activity
    Bioorganic & Medicinal Chemistry Letters, 2019
    Co-Authors: Tsuyoshi Saitoh, Yoko Irukayamatomobe, Noriki Kutsumura, Naoshi Yamamoto, Yasuyuki Nagumo, Kazunori Seki, Ryo Nakajima, Yasuhiro Ogawa, Yukiko Ishikawa, Ryuji Tanimura
    Abstract:

    Abstract The Orexin 1 Receptor (OX1R) antagonists carrying a morphinan skeleton such as YNT-707 (2) and YNT-1310 (3) showed potent and extremely high selective antagonistic activity against OX1R. In the course of our study of the essential structure of YNT-707 for high binding affinity against OX1R, we prepared derivatives of 2 without the D- and 4,5-epoxy rings to clarify the roles of these structural determinants toward OX1R antagonistic activity. The D- and 4,5-epoxy rings played important roles for the active orientation of the 17-sulfonamide and 6-amide side chains. Finally, we identified the simple structure required for selective OX1R antagonistic activity in the complex morphinan skeleton, which is expected to be a useful scaffold for further design of OX1R ligands.

  • essential structure of Orexin 1 Receptor antagonist ynt 707 part iii role of the 14 hydroxy and the 3 methoxy groups in antagonistic activity toward the Orexin 1 Receptor in ynt 707 derivatives lacking the 4 5 epoxy ring
    Bioorganic & Medicinal Chemistry, 2019
    Co-Authors: Naoshi Yamamoto, Yoko Irukayamatomobe, Noriki Kutsumura, Tsuyoshi Saitoh, Yasuyuki Nagumo, Yasuhiro Ogawa, Yukiko Ishikawa, Sayaka Ohrui, Takahiro Okada, Yurie Watanabe
    Abstract:

    Abstract Morphinan derivatives lacking the 4,5-epoxy ring were synthesized to examine the participation of the 14-OH group, the 3-OMe group, and the aromaticity of the A-ring in the activity and selectivity for the Orexin 1 Receptor (OX1R). The assay results and the conformational analyses of the 14-dehydrated and 14-H derivatives suggested that the orientations of the 6-amide side chain and the 17-benzenesulfonyl group would play important roles in the activity for OX1R. In the 6β-derivatives, removal of the 3-OMe group and the reduction of the A-ring significantly decreased the activity toward the OX1R, but these changes did not affect the 6α-derivatives. These results indicate that the 3-OMe group and the A-ring would be essential structural moieties for the 6β-derivatives.

  • essential structure of Orexin 1 Receptor antagonist ynt 707 part ii drastic effect of the 14 hydroxy group on the Orexin 1 Receptor antagonistic activity
    Bioorganic & Medicinal Chemistry Letters, 2017
    Co-Authors: Sayaka Ohrui, Yoko Irukayamatomobe, Noriki Kutsumura, Naoshi Yamamoto, Tsuyoshi Saitoh, Yasuyuki Nagumo, Yasuhiro Ogawa, Yukiko Ishikawa, Yurie Watanabe, Daichi Hayakawa
    Abstract:

    Abstract The 14-dehydration- and 14-H derivatives of the Orexin 1 Receptor (OX1R) antagonist YNT-707 (2) were synthesized. The obtained derivatives showed higher affinities for OX1R than the corresponding 14-hydroxy derivatives. The conformational analysis suggested that the 17-sulfonamide groups in the derivatives without the 14-hydroxy group have a greater tendency to be oriented toward the upper side of the D-ring compared with the 14-hydroxy derivatives. Additionally, the 14-dehydration-derivative with 6α-amide side chain showed significantly higher affinity than the 14-hydroxy derivative, while the corresponding 14-H derivative showed only slightly higher affinity. Thus, the 14-hydroxy group strongly affects the affinity of the antagonist for the OX1R.

  • essential structure of Orexin 1 Receptor antagonist ynt 707 part i role of the 4 5 epoxy ring for binding with Orexin 1 Receptor
    Bioorganic & Medicinal Chemistry Letters, 2017
    Co-Authors: Naoshi Yamamoto, Yoko Irukayamatomobe, Noriki Kutsumura, Tsuyoshi Saitoh, Yasuyuki Nagumo, Yasuhiro Ogawa, Sayaka Ohrui, Takahiro Okada, Masahiro Yata, Yukiko Ishikawa
    Abstract:

    Abstract The essential structure of the Orexin 1 Receptor (OX 1 R) antagonist YNT-707 ( 2 ) was clarified, particularly the roles to OX 1 R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-hydroxy group, and the orientation of the 6-amide side chain. The 3-OMe and 17-sulfonamide group were shown to be essential for the OX 1 R antagonistic activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide group. The 14-hydroxy group could lower the activity of the 6β-amide isomer by the interaction of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward the upper side of the C-ring. Finally, we proposed the difference in the active conformation between OX 1 R and κ opioid Receptor (KOR), especially in the orientation of the 6-amide group which is expected to be a useful guide for medicinal chemists to design OX 1 R ligands.

Tsuyoshi Saitoh - One of the best experts on this subject based on the ideXlab platform.

  • essential structure of Orexin 1 Receptor antagonist ynt 707 part v structure activity relationship study of the substituents on the 17 amino group
    Bioorganic & Medicinal Chemistry Letters, 2020
    Co-Authors: Tsuyoshi Saitoh, Yoko Irukayamatomobe, Noriki Kutsumura, Naoshi Yamamoto, Yasuyuki Nagumo, Kazunori Seki, Ryo Nakajima, Yasuhiro Ogawa, Yukiko Ishikawa, Masashi Yanagisawa
    Abstract:

    Abstract The morphinan-type Orexin 1 Receptor (OX1R) antagonists such as YNT-707 (2) and YNT-1310 (3) show potent and extremely high selective antagonistic activity against OX1R. In the course of our studies of the essential structure of 2, we identified new scaffolds by simplification of the morphinan skeleton. However, the new chemical entities carrying the D-ring removed scaffold showed insufficient activity. To improve the activity of these derivatives, we investigated the effect of substituents mainly focused on the 17-nitrogen group. The 17-N-substituted derivatives, as well as the cyclic derivatives, were synthesized and examined the OX1R antagonistic activity. The assay results showed the interesting relationship between the OX1R antagonistic activity and the substituents on the 17-nitrogen: the antagonistic activity was increased as the bulkiness of 17-substituents increased. Finally, the 17-N-Boc derivative 14a showed the most potent OX1R antagonistic activity (Ki = 14.8 nM).

  • essential structure of Orexin 1 Receptor antagonist ynt 707 part iv the role of d ring in 4 5 epoxymorphinan on the Orexin 1 Receptor antagonistic activity
    Bioorganic & Medicinal Chemistry Letters, 2019
    Co-Authors: Tsuyoshi Saitoh, Yoko Irukayamatomobe, Noriki Kutsumura, Naoshi Yamamoto, Yasuyuki Nagumo, Kazunori Seki, Ryo Nakajima, Yasuhiro Ogawa, Yukiko Ishikawa, Ryuji Tanimura
    Abstract:

    Abstract The Orexin 1 Receptor (OX1R) antagonists carrying a morphinan skeleton such as YNT-707 (2) and YNT-1310 (3) showed potent and extremely high selective antagonistic activity against OX1R. In the course of our study of the essential structure of YNT-707 for high binding affinity against OX1R, we prepared derivatives of 2 without the D- and 4,5-epoxy rings to clarify the roles of these structural determinants toward OX1R antagonistic activity. The D- and 4,5-epoxy rings played important roles for the active orientation of the 17-sulfonamide and 6-amide side chains. Finally, we identified the simple structure required for selective OX1R antagonistic activity in the complex morphinan skeleton, which is expected to be a useful scaffold for further design of OX1R ligands.

  • essential structure of Orexin 1 Receptor antagonist ynt 707 part iii role of the 14 hydroxy and the 3 methoxy groups in antagonistic activity toward the Orexin 1 Receptor in ynt 707 derivatives lacking the 4 5 epoxy ring
    Bioorganic & Medicinal Chemistry, 2019
    Co-Authors: Naoshi Yamamoto, Yoko Irukayamatomobe, Noriki Kutsumura, Tsuyoshi Saitoh, Yasuyuki Nagumo, Yasuhiro Ogawa, Yukiko Ishikawa, Sayaka Ohrui, Takahiro Okada, Yurie Watanabe
    Abstract:

    Abstract Morphinan derivatives lacking the 4,5-epoxy ring were synthesized to examine the participation of the 14-OH group, the 3-OMe group, and the aromaticity of the A-ring in the activity and selectivity for the Orexin 1 Receptor (OX1R). The assay results and the conformational analyses of the 14-dehydrated and 14-H derivatives suggested that the orientations of the 6-amide side chain and the 17-benzenesulfonyl group would play important roles in the activity for OX1R. In the 6β-derivatives, removal of the 3-OMe group and the reduction of the A-ring significantly decreased the activity toward the OX1R, but these changes did not affect the 6α-derivatives. These results indicate that the 3-OMe group and the A-ring would be essential structural moieties for the 6β-derivatives.

  • essential structure of Orexin 1 Receptor antagonist ynt 707 part ii drastic effect of the 14 hydroxy group on the Orexin 1 Receptor antagonistic activity
    Bioorganic & Medicinal Chemistry Letters, 2017
    Co-Authors: Sayaka Ohrui, Yoko Irukayamatomobe, Noriki Kutsumura, Naoshi Yamamoto, Tsuyoshi Saitoh, Yasuyuki Nagumo, Yasuhiro Ogawa, Yukiko Ishikawa, Yurie Watanabe, Daichi Hayakawa
    Abstract:

    Abstract The 14-dehydration- and 14-H derivatives of the Orexin 1 Receptor (OX1R) antagonist YNT-707 (2) were synthesized. The obtained derivatives showed higher affinities for OX1R than the corresponding 14-hydroxy derivatives. The conformational analysis suggested that the 17-sulfonamide groups in the derivatives without the 14-hydroxy group have a greater tendency to be oriented toward the upper side of the D-ring compared with the 14-hydroxy derivatives. Additionally, the 14-dehydration-derivative with 6α-amide side chain showed significantly higher affinity than the 14-hydroxy derivative, while the corresponding 14-H derivative showed only slightly higher affinity. Thus, the 14-hydroxy group strongly affects the affinity of the antagonist for the OX1R.

  • essential structure of Orexin 1 Receptor antagonist ynt 707 part i role of the 4 5 epoxy ring for binding with Orexin 1 Receptor
    Bioorganic & Medicinal Chemistry Letters, 2017
    Co-Authors: Naoshi Yamamoto, Yoko Irukayamatomobe, Noriki Kutsumura, Tsuyoshi Saitoh, Yasuyuki Nagumo, Yasuhiro Ogawa, Sayaka Ohrui, Takahiro Okada, Masahiro Yata, Yukiko Ishikawa
    Abstract:

    Abstract The essential structure of the Orexin 1 Receptor (OX 1 R) antagonist YNT-707 ( 2 ) was clarified, particularly the roles to OX 1 R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-hydroxy group, and the orientation of the 6-amide side chain. The 3-OMe and 17-sulfonamide group were shown to be essential for the OX 1 R antagonistic activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide group. The 14-hydroxy group could lower the activity of the 6β-amide isomer by the interaction of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward the upper side of the C-ring. Finally, we proposed the difference in the active conformation between OX 1 R and κ opioid Receptor (KOR), especially in the orientation of the 6-amide group which is expected to be a useful guide for medicinal chemists to design OX 1 R ligands.

Yoko Irukayamatomobe - One of the best experts on this subject based on the ideXlab platform.

  • essential structure of Orexin 1 Receptor antagonist ynt 707 part v structure activity relationship study of the substituents on the 17 amino group
    Bioorganic & Medicinal Chemistry Letters, 2020
    Co-Authors: Tsuyoshi Saitoh, Yoko Irukayamatomobe, Noriki Kutsumura, Naoshi Yamamoto, Yasuyuki Nagumo, Kazunori Seki, Ryo Nakajima, Yasuhiro Ogawa, Yukiko Ishikawa, Masashi Yanagisawa
    Abstract:

    Abstract The morphinan-type Orexin 1 Receptor (OX1R) antagonists such as YNT-707 (2) and YNT-1310 (3) show potent and extremely high selective antagonistic activity against OX1R. In the course of our studies of the essential structure of 2, we identified new scaffolds by simplification of the morphinan skeleton. However, the new chemical entities carrying the D-ring removed scaffold showed insufficient activity. To improve the activity of these derivatives, we investigated the effect of substituents mainly focused on the 17-nitrogen group. The 17-N-substituted derivatives, as well as the cyclic derivatives, were synthesized and examined the OX1R antagonistic activity. The assay results showed the interesting relationship between the OX1R antagonistic activity and the substituents on the 17-nitrogen: the antagonistic activity was increased as the bulkiness of 17-substituents increased. Finally, the 17-N-Boc derivative 14a showed the most potent OX1R antagonistic activity (Ki = 14.8 nM).

  • essential structure of Orexin 1 Receptor antagonist ynt 707 part iv the role of d ring in 4 5 epoxymorphinan on the Orexin 1 Receptor antagonistic activity
    Bioorganic & Medicinal Chemistry Letters, 2019
    Co-Authors: Tsuyoshi Saitoh, Yoko Irukayamatomobe, Noriki Kutsumura, Naoshi Yamamoto, Yasuyuki Nagumo, Kazunori Seki, Ryo Nakajima, Yasuhiro Ogawa, Yukiko Ishikawa, Ryuji Tanimura
    Abstract:

    Abstract The Orexin 1 Receptor (OX1R) antagonists carrying a morphinan skeleton such as YNT-707 (2) and YNT-1310 (3) showed potent and extremely high selective antagonistic activity against OX1R. In the course of our study of the essential structure of YNT-707 for high binding affinity against OX1R, we prepared derivatives of 2 without the D- and 4,5-epoxy rings to clarify the roles of these structural determinants toward OX1R antagonistic activity. The D- and 4,5-epoxy rings played important roles for the active orientation of the 17-sulfonamide and 6-amide side chains. Finally, we identified the simple structure required for selective OX1R antagonistic activity in the complex morphinan skeleton, which is expected to be a useful scaffold for further design of OX1R ligands.

  • essential structure of Orexin 1 Receptor antagonist ynt 707 part iii role of the 14 hydroxy and the 3 methoxy groups in antagonistic activity toward the Orexin 1 Receptor in ynt 707 derivatives lacking the 4 5 epoxy ring
    Bioorganic & Medicinal Chemistry, 2019
    Co-Authors: Naoshi Yamamoto, Yoko Irukayamatomobe, Noriki Kutsumura, Tsuyoshi Saitoh, Yasuyuki Nagumo, Yasuhiro Ogawa, Yukiko Ishikawa, Sayaka Ohrui, Takahiro Okada, Yurie Watanabe
    Abstract:

    Abstract Morphinan derivatives lacking the 4,5-epoxy ring were synthesized to examine the participation of the 14-OH group, the 3-OMe group, and the aromaticity of the A-ring in the activity and selectivity for the Orexin 1 Receptor (OX1R). The assay results and the conformational analyses of the 14-dehydrated and 14-H derivatives suggested that the orientations of the 6-amide side chain and the 17-benzenesulfonyl group would play important roles in the activity for OX1R. In the 6β-derivatives, removal of the 3-OMe group and the reduction of the A-ring significantly decreased the activity toward the OX1R, but these changes did not affect the 6α-derivatives. These results indicate that the 3-OMe group and the A-ring would be essential structural moieties for the 6β-derivatives.

  • essential structure of Orexin 1 Receptor antagonist ynt 707 part ii drastic effect of the 14 hydroxy group on the Orexin 1 Receptor antagonistic activity
    Bioorganic & Medicinal Chemistry Letters, 2017
    Co-Authors: Sayaka Ohrui, Yoko Irukayamatomobe, Noriki Kutsumura, Naoshi Yamamoto, Tsuyoshi Saitoh, Yasuyuki Nagumo, Yasuhiro Ogawa, Yukiko Ishikawa, Yurie Watanabe, Daichi Hayakawa
    Abstract:

    Abstract The 14-dehydration- and 14-H derivatives of the Orexin 1 Receptor (OX1R) antagonist YNT-707 (2) were synthesized. The obtained derivatives showed higher affinities for OX1R than the corresponding 14-hydroxy derivatives. The conformational analysis suggested that the 17-sulfonamide groups in the derivatives without the 14-hydroxy group have a greater tendency to be oriented toward the upper side of the D-ring compared with the 14-hydroxy derivatives. Additionally, the 14-dehydration-derivative with 6α-amide side chain showed significantly higher affinity than the 14-hydroxy derivative, while the corresponding 14-H derivative showed only slightly higher affinity. Thus, the 14-hydroxy group strongly affects the affinity of the antagonist for the OX1R.

  • essential structure of Orexin 1 Receptor antagonist ynt 707 part i role of the 4 5 epoxy ring for binding with Orexin 1 Receptor
    Bioorganic & Medicinal Chemistry Letters, 2017
    Co-Authors: Naoshi Yamamoto, Yoko Irukayamatomobe, Noriki Kutsumura, Tsuyoshi Saitoh, Yasuyuki Nagumo, Yasuhiro Ogawa, Sayaka Ohrui, Takahiro Okada, Masahiro Yata, Yukiko Ishikawa
    Abstract:

    Abstract The essential structure of the Orexin 1 Receptor (OX 1 R) antagonist YNT-707 ( 2 ) was clarified, particularly the roles to OX 1 R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-hydroxy group, and the orientation of the 6-amide side chain. The 3-OMe and 17-sulfonamide group were shown to be essential for the OX 1 R antagonistic activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide group. The 14-hydroxy group could lower the activity of the 6β-amide isomer by the interaction of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward the upper side of the C-ring. Finally, we proposed the difference in the active conformation between OX 1 R and κ opioid Receptor (KOR), especially in the orientation of the 6-amide group which is expected to be a useful guide for medicinal chemists to design OX 1 R ligands.