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Institute of Pharmacy, Department of Pharmaceutical Chemistry, Center for Molecular Biosciences (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria

Prof. Dr. Hideaki Fujii

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Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan

Prof. Dr. Jay P. McLaughlin

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Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610-0487, USA

Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery

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closed (31 December 2023)

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31 October 2024

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Dear Colleagues,

Following the successful previous two editions of the Special Issue “Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery” (https://www.mdpi.com/journal/molecules/special_issues/Opioid_Drug) in Molecules, this new joint Special Issue of the International Journal of Molecular Sciences, Journal of Clinical Medicine, Molecules, Pharmaceuticals, Pharmaceutics, and Chemistry aims to gather works on the latest chemical and pharmacological developments in opioid research, with a further understanding of opioids and opioid-receptor-mediated actions and the search for alternative treatments for pain and other human disorders where the opioid system plays an central role. Special attention is drawn to advancing concepts in opioid drug discovery in the light of the current opioid crisis. We thank you for your past contributions and welcome original articles, short communications, and review articles on current and emerging concepts in opioid drug discovery and in general opioid research, ranging from basic science to translational research.

Prof. Dr. Mariana Spetea
Prof. Dr. Hideaki Fujii
Prof. Dr. Jay P. McLaughlin
Topic Editors

Keywords

opioid receptors and opioids ligands
opioid epidemic
natural and synthetic compounds
agonists, antagonists, and partial agonists
biased agonists and allosteric modulators
multifunctional and bivalent ligands
drug design
synthesis and analytics
molecular docking and dynamics simulations
structure–activity relationships
pain
CNS disorders
opioid side effects
opioids and substance abuse
opioids and respiration

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
International Journal of Molecular Sciences ijms	5.6	7.8	2000	16.3 Days	CHF 2900	Submit
Journal of Clinical Medicine jcm	3.9	5.4	2012	17.9 Days	CHF 2600	Submit
Molecules molecules	4.6	6.7	1996	14.6 Days	CHF 2700	Submit
Pharmaceuticals pharmaceuticals	4.6	4.7	2004	14.6 Days	CHF 2900	Submit
Pharmaceutics pharmaceutics	5.4	6.9	2009	14.2 Days	CHF 2900	Submit
Chemistry chemistry	2.1	2.5	2019	19.1 Days	CHF 1800	Submit

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Published Papers (9 papers)

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17 pages, 1907 KiB

Open AccessArticle

In Vitro and In Vivo Pharmacological Profiles of LENART01, a Dermorphin–Ranatensin Hybrid Peptide

by Nadine Hochrainer, Pawel Serafin, Sara D’Ingiullo, Adriano Mollica, Sebastian Granica, Marek Brytan, Patrycja Kleczkowska and Mariana Spetea

Int. J. Mol. Sci. 2024, 25(7), 4007; https://doi.org/10.3390/ijms25074007 - 03 Apr 2024

Viewed by 479

Abstract

Diverse chemical and pharmacological strategies are currently being explored to minimize the unwanted side effects of currently used opioid analgesics while achieving effective pain relief. The use of multitarget ligands with activity at more than one receptor represents a promising therapeutic approach. We recently reported a bifunctional peptide-based hybrid LENART01 combining dermorphin and ranatensin pharmacophores, which displays activity to the mu-opioid receptor (MOR) and dopamine D2 receptor (D2R) in rat brains and spinal cords. In this study, we investigated the in vitro binding and functional activities to the human MOR and the in vivo pharmacology of LENART01 in mice after subcutaneous administration. In vitro binding assays showed LENART01 to bind and be selective to the human MOR over the other opioid receptor subtypes and delta, kappa and nociceptin receptors. In the [³⁵S]GTPγS binding assay, LENART01 acted as a potent and full agonist to the human MOR. In mice, LENART01 produced dose-dependent antinociceptive effects in formalin-induced inflammatory pain, with increased potency than morphine. Antinociceptive effects were reversed by naloxone, indicating MOR activation in vivo. Behavioral studies also demonstrated LENART01’s properties to induce less adverse effects without locomotor dysfunction and withdrawal syndrome compared to conventional opioid analgesics, such as morphine. LENART01 is the first peptide-based MOR-D2R ligand known to date and the first dual MOR-dopamine D2R ligand for which in vivo pharmacology is reported with antinociceptive efficacy and reduced opioid-related side effects. Our current findings may pave the way to new pain therapeutics with limited side effects in acute and chronic use. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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18 pages, 3518 KiB

Open AccessArticle

SYK-623, a δ Opioid Receptor Inverse Agonist, Mitigates Chronic Stress-Induced Behavioral Abnormalities and Disrupted Neurogenesis

by Takashi Iwai, Rei Mishima, Shigeto Hirayama, Honoka Nakajima, Misa Oyama, Shun Watanabe, Hideaki Fujii and Mitsuo Tanabe

J. Clin. Med. 2024, 13(2), 608; https://doi.org/10.3390/jcm13020608 - 21 Jan 2024

Viewed by 754

Abstract

The δ opioid receptor (DOR) inverse agonist has been demonstrated to improve learning and memory impairment in mice subjected to restraint stress. Here, we investigated the effects of SYK-623, a new DOR inverse agonist, on behavioral, immunohistochemical, and biochemical abnormalities in a mouse model of imipramine treatment-resistant depression. Male ddY mice received daily treatment of adrenocorticotropic hormone (ACTH) combined with chronic mild stress exposure (ACMS). SYK-623, imipramine, or the vehicle was administered once daily before ACMS. After three weeks, ACMS mice showed impaired learning and memory in the Y-maze test and increased immobility time in the forced swim test. SYK-623, but not imipramine, significantly suppressed behavioral abnormalities caused by ACMS. Based on the fluorescent immunohistochemical analysis of the hippocampus, ACMS induced a reduction in astrocytes and newborn neurons, similar to the reported findings observed in the postmortem brains of depressed patients. In addition, the number of parvalbumin-positive GABA neurons, which play a crucial role in neurogenesis, was reduced in the hippocampus, and western blot analysis showed decreased glutamic acid decarboxylase protein levels. These changes, except for the decrease in astrocytes, were suppressed by SYK-623. Thus, SYK-623 mitigates behavioral abnormalities and disturbed neurogenesis caused by chronic stress. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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31 pages, 7792 KiB

Open AccessArticle

Potent MOR Agonists from 2′-Hydroxy-5,9-dimethyl-N-phenethyl Substituted-6,7-benzomorphans and from C8-Hydroxy, Methylene and Methyl Derivatives of N-Phenethylnormetazocine

by Madhurima Das, George W. Ward, Agnieszka Sulima, Dan Luo, Thomas Edward Prisinzano, Gregory H. Imler, Andrew T. Kerr, Arthur E. Jacobson and Kenner C. Rice

Molecules 2023, 28(23), 7709; https://doi.org/10.3390/molecules28237709 - 22 Nov 2023

Viewed by 786

Abstract

(−)-5,9-Dimethyl-6,7-benzomorphan (normetazocine) derivatives with a para-OH or ortho-F substituent in the aromatic ring of the N-phenethyl moiety were synthesized and found to have subnanomolar potency at MOR, and both were fully efficacious in vitro. These new compounds, (1R,5R,9R)-6,11-dimethyl-3-(2-fluorophenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol and (1R,5R,9R)-6,11-dimethyl-3-(4-hydroxyphenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol, were more potent than the unsubstituted compound N-phenethylnormetazocine and about 30 or 40 times more potent than morphine, respectively. A variety of substituents in the ortho, meta, or para position in the aromatic ring of the N-phenethyl moiety were synthesized, 25 of these compounds, and found to have varying effects on potency and efficacy as determined by the forskolin-induced cAMP accumulation assay. The N-phenethyl moiety was also modified by increasing chain length to form a N-phenylpropyl side chain with and without a para-nitro moiety, and by an N-cinnamyl side chain. Also, an indole ethylamine normetazocine was synthesized to replace the N-phenethylamine side chain in normetazocine. The phenylpropylamine, propenylamine (cinnamyl) and the para-nitropropylamine had little or no MOR potency. The indole-ethylamine on the normetazocine nucleus, however, had moderate potency (MOR EC₅₀ = 12 nM), and was fully efficacious (%E_max = 102%) in the cAMP assay. Retention of the N-phenethyl moiety and the addition of alkyl and alkenyl moieties on C8 in (−)-N-phenethylnormetazocine gave a C8-methylene derivative that had subnanomolar potency at MOR and a C8-methyl analog that had nanomolar potency. Five C8-substituted compounds were synthesized. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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18 pages, 3479 KiB

Open AccessArticle

Identification and Pharmacological Characterization of a Low-Liability Antinociceptive Bifunctional MOR/DOR Cyclic Peptide

by Yangmei Li, Shainnel O. Eans, Michelle Ganno-Sherwood, Abbe Eliasof, Richard A. Houghten and Jay P. McLaughlin

Molecules 2023, 28(22), 7548; https://doi.org/10.3390/molecules28227548 - 11 Nov 2023

Cited by 1 | Viewed by 999

Abstract

Peptide-based opioid ligands are important candidates for the development of novel, safer, and more effective analgesics to treat pain. To develop peptide-based safer analgesics, we synthesized a mixture-based cyclic pentapeptide library containing a total of 24,624 pentapeptides and screened the mixture-based library samples using a 55 °C warm water tail-withdrawal assay. Using this phenotypic screening approach, we deconvoluted the mixture-based samples to identify a novel cyclic peptide Tyr-[D-Lys-Dap(Ant)-Thr-Gly] (CycloAnt), which produced dose- and time-dependent antinociception with an ED₅₀ (and 95% confidence interval) of 0.70 (0.52–0.97) mg/kg i.p. mediated by the mu-opioid receptor (MOR). Additionally, higher doses (≥3 mg/kg, i.p.) of CycloAnt antagonized delta-opioid receptors (DOR) for at least 3 h. Pharmacological characterization of CycloAnt showed the cyclic peptide did not reduce breathing rate in mice at doses up to 15 times the analgesic ED₅₀ value, and produced dramatically less hyperlocomotion than the MOR agonist, morphine. While chronic administration of CycloAnt resulted in antinociceptive tolerance, it was without opioid-induced hyperalgesia and with significantly reduced signs of naloxone-precipitated withdrawal, which suggested reduced physical dependence compared to morphine. Collectively, the results suggest this dual MOR/DOR multifunctional ligand is an excellent lead for the development of peptide-based safer analgesics. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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48 pages, 15800 KiB

Open AccessReview

From Plant to Chemistry: Sources of Active Opioid Antinociceptive Principles for Medicinal Chemistry and Drug Design

by Rita Turnaturi, Silvia Piana, Salvatore Spoto, Giuliana Costanzo, Lorena Reina, Lorella Pasquinucci and Carmela Parenti

Molecules 2023, 28(20), 7089; https://doi.org/10.3390/molecules28207089 - 14 Oct 2023

Cited by 4 | Viewed by 2062

Abstract

Pain continues to be an enormous global health challenge, with millions of new untreated or inadequately treated patients reported annually. With respect to current clinical applications, opioids remain the mainstay for the treatment of pain, although they are often associated with serious side effects. To optimize their tolerability profiles, medicinal chemistry continues to study novel ligands and innovative approaches. Among them, natural products are known to be a rich source of lead compounds for drug discovery, and they hold potential for pain management. Traditional medicine has had a long history in clinical practice due to the fact that nature provides a rich source of active principles. For instance, opium had been used for pain management until the 19th century when its individual components, such as morphine, were purified and identified. In this review article, we conducted a literature survey aimed at identifying natural products interacting either directly with opioid receptors or indirectly through other mechanisms controlling opioid receptor signaling, whose structures could be interesting from a drug design perspective. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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19 pages, 2431 KiB

Open AccessArticle

Discovery of 7-Azanorbornane-Based Dual Agonists for the Delta and Kappa Opioid Receptors through an In Situ Screening Protocol

by Fumika Karaki, Taro Takamori, Koumei Kawakami, Sae Sakurai, Kyoko Hidaka, Kei Ishii, Tomoya Oki, Noriko Sato, Nao Atsumi, Karin Ashizawa, Ai Taguchi, Asuka Ura, Toko Naruse, Shigeto Hirayama, Miki Nonaka, Kanako Miyano, Yasuhito Uezono and Hideaki Fujii

Molecules 2023, 28(19), 6925; https://doi.org/10.3390/molecules28196925 - 03 Oct 2023

Viewed by 962

Abstract

In medicinal chemistry, the copper-catalyzed click reaction is used to prepare ligand candidates. This reaction is so clean that the bioactivities of the products can be determined without purification. Despite the advantages of this in situ screening protocol, the applicability of this method for transmembrane proteins has not been validated due to the incompatibility with copper catalysts. To address this point, we performed ligand screening for the µ, δ, and κ opioid receptors using this protocol. As we had previously reported the 7-azanorbornane skeleton as a privileged scaffold for the G protein-coupled receptors, we performed the click reactions between various 7-substituted 2-ethynyl-7-azanorbornanes and azides. Screening assays were performed without purification using the CellKey^TM system, and the putative hit compounds were re-synthesized and re-evaluated. Although the “hit” compounds for the µ and the δ receptors were totally inactive after purifications, three of the four “hits” for the κ receptor were true agonists for this receptor and also showed activities for the δ receptor. Although false positive/negative results exist as in other screening projects for soluble proteins, this in situ method is effective in identifying novel ligands for transmembrane proteins. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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22 pages, 3844 KiB

Open AccessArticle

The Kappa Opioid Receptor Agonist 16-Bromo Salvinorin A Has Anti-Cocaine Effects without Significant Effects on Locomotion, Food Reward, Learning and Memory, or Anxiety and Depressive-like Behaviors

by Ross van de Wetering, Amy Ewald, Susan Welsh, Lindsay Kornberger, Samuel E. Williamson, Bryan D. McElroy, Eduardo R. Butelman, Thomas E. Prisinzano and Bronwyn M. Kivell

Molecules 2023, 28(12), 4848; https://doi.org/10.3390/molecules28124848 - 19 Jun 2023

Cited by 1 | Viewed by 1756

Abstract

Kappa opioid receptor (KOR) agonists have preclinical antipsychostimulant effects; however, adverse side effects have limited their therapeutic development. In this preclinical study, conducted in Sprague Dawley rats, B6-SJL mice, and non-human primates (NHPs), we evaluated the G-protein-biased analogue of salvinorin A (SalA), 16-bromo salvinorin A (16-BrSalA), for its anticocaine effects, side effects, and activation of cellular signaling pathways. 16-BrSalA dose-dependently decreased the cocaine-primed reinstatement of drug-seeking behavior in a KOR-dependent manner. It also decreased cocaine-induced hyperactivity, but had no effect on responding for cocaine on a progressive ratio schedule. Compared to SalA, 16-BrSalA had an improved side effect profile, with no significant effects in the elevated plus maze, light–dark test, forced swim test, sucrose self-administration, or novel object recognition; however, it did exhibit conditioned aversive effects. 16-BrSalA increased dopamine transporter (DAT) activity in HEK-293 cells coexpressing DAT and KOR, as well as in rat nucleus accumbens and dorsal striatal tissue. 16-BrSalA also increased the early phase activation of extracellular-signal-regulated kinases 1 and 2, as well as p38 in a KOR-dependent manner. In NHPs, 16-BrSalA caused dose-dependent increases in the neuroendocrine biomarker prolactin, similar to other KOR agonists, at doses without robust sedative effects. These findings highlight that G-protein-biased structural analogues of SalA can have improved pharmacokinetic profiles and fewer side effects while maintaining their anticocaine effects. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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18 pages, 10337 KiB

Open AccessArticle

Altered Membrane Expression and Function of CD11b Play a Role in the Immunosuppressive Effects of Morphine on Macrophages at the Nanomolar Level

by Peng-Cheng Yu, Cui-Yun Hao, Ying-Zhe Fan, Di Liu, Yi-Fan Qiao, Jia-Bao Yao, Chang-Zhu Li and Ye Yu

Pharmaceuticals 2023, 16(2), 282; https://doi.org/10.3390/ph16020282 - 13 Feb 2023

Cited by 2 | Viewed by 2054

Abstract

Morphine, one of the most efficacious analgesics, is effective in severe pain, especially in patients with concomitant painful cancers. The clinical use of morphine may be accompanied by increased immunosuppression, susceptibility to infection and postoperative tumor metastatic recurrence, and the specific mechanisms and clinical strategies to alleviate this suppression remain to be investigated. Expression of CD11b is closely associated with the macrophage phagocytosis of xenobiotic particles, bacteria or tumor cells. Here, we find that morphine at 0.1–10 nM levels inhibited CD11b expression and function on macrophages via a μ-opioid receptor (MOR)-dependent mechanism, thereby reducing macrophage phagocytosis of tumor cells, a process that can be reversed by thymopentin (TP5), a commonly used immune-enhancing adjuvant in clinical practice. By knocking down or overexpressing MOR on macrophages and using naloxone, an antagonist of the MOR receptor, and LA1, a molecule that promotes macrophage CD11b activation, we suggest that morphine may regulate macrophage phagocytosis by inhibiting the surface expression and function of macrophage CD11b through the membrane expression and activation of MOR. The CD47/SIRPα axis, which is engaged in macrophage-tumor immune escape, was not significantly affected by morphine. Notably, TP5, when combined with morphine, reversed the inhibition of macrophage phagocytosis by morphine through mechanisms that promote membrane expression of CD11b and modulate its downstream signaling (e.g., NOS2, IFNG, IL1B and TNFA, as well as AGR1, PDGFB, IL6, STAT3, and MYC). Thus, altered membrane expression and function of CD11b may mediate the inhibition of macrophage phagocytosis by therapeutic doses of morphine, and the reversal of this process by TP5 may provide an effective palliative option for clinical immunosuppression by morphine. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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15 pages, 5677 KiB

Open AccessArticle

Delta Opioid Peptide Targets Brain Microvascular Endothelial Cells Reducing Apoptosis to Relieve Hypoxia-Ischemic/Reperfusion Injury

by Ran Zhang, Meixuan Chen, Zhongfang Deng, Lingchao Kong, Bing Shen and Lesha Zhang

Pharmaceutics 2023, 15(1), 46; https://doi.org/10.3390/pharmaceutics15010046 - 23 Dec 2022

Cited by 1 | Viewed by 1857

Abstract

Stroke is one of the leading causes of death. (D-ala2, D-leu5) enkephalin (DADLE) is a synthetic peptide and highly selective delta opioid receptor (δOR) agonist that has exhibited protective properties in ischemia. However, the specific target and mechanism are still unclear. The present study explores the expression of δOR on brain microvascular endothelial cells (BMECs) and whether DADLE could relieve I/R-induced injury by reducing apoptosis. A lateral ventricular injection of DADLE for pretreatment, the neurofunctional behavior score, and TTC staining, were used to evaluate the protective effect of DADLE. Immunofluorescence technology was used to label different types of cells with apoptosis-positive signals to test co-localization status. Primary cultured BMECs were separated and treated with DADLE, accompanied by OGD/R. The CCK-8 test was conducted to evaluate cell viability and TdT-mediated dUTP Nick-end Labelling (TUNEL) staining to test apoptosis levels. The levels of apoptosis-related proteins were analyzed by Western blotting. The co-localization results showed that BMECs, but not astrocytes, microglia, or neurons, presented mostly TUNEL-positive signals, especially in the Dentate gyrus (DG) area of the hippocampus. Either activation of δORs on rats’ brains or primary BMECs mainly reduce cellular apoptosis and relieve the injury. Interference with the expression δOR could block this effect. DADLE also significantly increased levels of Bcl-2 and reduced levels of Bax. δOR’s expressions can be detected on the BMECs, but not on the HEK293 cells, by Western blotting and IFC. Therefore, DADLE exerts a cytoprotective effect, primarily under hypoxia-ischemic injury/reperfusion conditions, by targeting BMECs to inhibit apoptosis. Full article

(This article belongs to the Topic Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Discovery of dual agonists for delta and kappa opioid receptors with 7-azanorbornane scaffolds (This is the tentative title)
Authors: Fumika Karaki1,2,*; Taro Takamori1; Koumei Kawakami1; Sae Sakurai1; Kyoko Hidaka1; Kei Ishii1; Noriko Sato3; Nao Atsumi1,4; Karin Ashizawa1,4; Ai Taguchi1,4; Asuka Ura1,4; Toko Naruse1; Shigeto Hirayama1,2; Miki Nonaka4; Kanako Miyano4; Yasuhito Uezono4; Hideaki Fujii1,2,*
Affiliation: 1 Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan 2 Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japa
Abstract: Modern screening collections are filled with sp2-rich, planar molecules due to the ease of synthesis. Despite this, sp3-rich, three-dimensional compounds are shown to be advantageous as drug candidates. We have proposed that modifying the three-dimensional 7-azanorbornane skeleton with copper-catalyzed click chemistry is an easy and reliable approach to constructing a three-dimensional compound library. Considering that we have discovered weak agonists for the kappa opioid receptor (KOR) from our small library, in this study, we aimed to obtain agonists for KOR and other opioid receptors from a larger compound set. We performed the click reactions in microplates using sixteen alkynes and eleven azides and determined the products' agonistic activities without purifications. The hit compounds were then re-synthesized and their activities were validated. Four of the compounds were dual agonists for the delta opioid receptor (DOR) and KOR without significant activities for the mu opioid receptor (MOR). Targeting the DOR or KOR, not the MOR, is one of the ongoing strategies to develop side-effect-free analgesics. Thus, screening around the 7-azanorbornane scaffold may be a reasonable approach to tackle the current "opioid crisis".

Title: SYK-623, a delta opioid receptor inverse agonist, mitigates behavioral abnormalities and disturbed process of neurogenesis caused by chronic stress.
Authors: Takashi Iwai1,3, Rei Mishima1,3, Shigeto Hirayama2,3, Honoka Nakajima1,3, Mamoru Honaga1,3, Misa Oyama1,3, Shun Watanabe1,3, Hideaki Fujii2,3, Mitsuo Tanabe1,３*
Affiliation: 1 Laboratory of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan 2 Laboratory of Medicinal Chemistory, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Mina-to-ku, Tokyo 108-
Abstract: We have previously demonstrated that the opioid receptor (DOR) inverse agonist can improve learning memory impairment in restraint stress mice. Here, we investigated the effects of SYK-623, a new DOR inverse agonist, on behavioral and immunohistochemical/biochemical abnormalities in imipramine treatment-resistant depression model mice. Male ddY mice received daily treatment of ACTH combined with chronic mild stress exposure (ACMS). SYK-623, imipramine, or vehicle were administered once daily prior to ACMS. After 3 weeks, ACMS mice showed impaired learning and memory in the Y-maze test and increased immobility time in the forced swim test. SYK-623, but not imipramine, significantly suppressed these behavioral abnormalities caused by ACMS. Based on fluorescent immunohistochemical analysis in the hippocampus, ACMS induced a reduction of astrocytes and newborn neurons, resembling the reported findings observed in postmortem brains of depressed patients. In addition, the number of parvalbumin-positive GABA neurons which play a crucial role in neurogenesis was reduced in the hippocampus, with Western blot analysis showing decreased protein levels of glutamic acid decarboxylase. These changes, except for a decrease in astrocytes, were suppressed by SYK-623. Thus, SYK-623 mitigates behavioral abnormalities and disturbed process of neurogenesis caused by chronic stress.

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Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
International Journal of Molecular Sciences ijms	5.6	7.8	2000	16.3 Days	CHF 2900
Journal of Clinical Medicine jcm	3.9	5.4	2012	17.9 Days	CHF 2600
Molecules molecules	4.6	6.7	1996	14.6 Days	CHF 2700
Pharmaceuticals pharmaceuticals	4.6	4.7	2004	14.6 Days	CHF 2900
Pharmaceutics pharmaceutics	5.4	6.9	2009	14.2 Days	CHF 2900
Chemistry chemistry	2.1	2.5	2019	19.1 Days	CHF 1800

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Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery

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