The Discovery of Novel α Adrenergic Receptor Agonists Only Coupling to Gαi/O Proteins by Virtual Screening.

Most α-AR agonists derived from dexmedetomidine have few structural differences between them and have no selectivity for α-AR or Gi/Gs, which can lead to side effects in drugs. To obtain novel and potent α-AR agonists, we performed virtual screening for human α-AR and α-AR to find α-AR agonists with higher selectivity. Compound P300-2342 and its three analogs significantly decreased the locomotor activity of mice ( < 0.

5-hydroxytryptamine 2C/1A receptors modulate the biphasic dose response of the head twitch response and locomotor activity induced by DOM in mice.

Rationale: The phenylalkylamine hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) exhibits an inverted U-shaped dose-response curve for both head twitch response (HTR) and locomotor activity in mice. Accumulated studies suggest that HTR and locomotor hyperactivity induced by DOM are mainly caused by the activation of serotonin 5-hydroxytryptamine 2 A receptor (5-HT receptor). However, the mechanisms underlying the biphasic dose response of HTR and locomotor activity induced by DOM, particularly at high doses, remain unclear.

Designing Chromane Derivatives as α-Adrenoceptor Selective Agonists via Conformation Constraint.

Enhancing the selectivity of alpha-adrenoceptor (α-AR) agonists remains an unresolved issue. Herein, we reported the design of an α-AR agonist using the conformation constraint method, beginning with medetomidine. The structure-activity relationship indicated that the 8-substituent of chromane derivatives exerted the most pronounced effect on α-AR agonistic activity.

Novel Scaffold Agonists of the α Adrenergic Receptor Identified via Ensemble-Based Strategy.

The α adrenergic receptor (α-AR) serves as a critical molecular target for sedatives and analgesics. However, α-AR ligands with an imidazole ring also interact with an imidazoline receptor as well as other proteins and lead to undesirable effects, motivating us to develop more novel scaffold α-AR ligands. For this purpose, we employed an ensemble-based ligand discovery strategy, integrating long-term molecular dynamics (MD) simulations and virtual screening, to identify new potential α-AR agonists with novel scaffold.

Gβγ subunit inhibitor decreases DOM-induced head twitch response via the PLCβ/IP3/Ca/ERK and cAMP signaling pathways.

Aims: (-)-2,5-dimethoxy-4-methylamphetamine (DOM) induces the head-twitch response (HTR) primarily by activating the serotonin 5-hydroxytryptamine 2A receptor (5-HT receptor) in mice. However, the mechanisms underlying 5-HT receptor activation and the HTR remain elusive. Gβγ subunits are a potential treatment target in numerous diseases.

A20-Binding Inhibitor of Nuclear Factor-B Targets -Arrestin2 to Attenuate Opioid Tolerance.

Opioids play an important role in pain relief, but repeated exposure results in tolerance and dependence. To make opioids more effective and useful, research in the field has focused on reducing the tolerance and dependence for chronic pain relief. Here, we showed the effect of A20-binding inhibitor of nuclear factor-B (ABIN-1) in modulating morphine function.

Thienorphine induces antinociception without dependence through activation of κ- and δ-, and partial activation of μ- opioid receptor.

Thienorphine hydrochloride is a new anti-relapse drug for opioid abusers that is currently in phase II clinical trial. In the present study, the antinociception, dependence, and signal transduction induced by thienorphine were examined. Thienorphine showed a potent antinociception effect in acetic acid-induced writhing test and formalin test.

Hsp90β positively regulates μ-opioid receptor function.

Aims: Many μ-opioid receptor (MOR)-associated proteins can regulate the MOR signaling pathway. Using a bacterial two-hybrid screen, we found that the C-terminal of the MOR associated with heat shock protein 90 isoform β (Hsp90β). Here, we explored the effect of Hsp90β on MOR signaling transduction and function.

G and G subunits have opposing effects on dexmedetomidine-induced sedation.

Dexmedetomidine (DMED) is a potent and highly selective α-adrenergic receptor agonist and is widely used for short-term sedation. However, the mechanism of DMED-induced sedation has not been deciphered. In the present study, we investigated the mechanism of G and G subunits on DMED-induced sedation.

Knocking down Cabin1 induces glomerular podocyte injury.

Background: Podocyte damage exerts a key role in proteinuria. We have demonstrated that calcineurin-binding protein 1 (Cabin1) upregulated during podocyte injury, yet its function in podocyte is still unclear.

Methods: We established 5/6 nephrectomized rats and angiotensin II (AngII)-injured podocyte, as well as knocked down Cabin1 with siRNA in cultured podocytes.

ABIN-1 Negatively Regulates -Opioid Receptor Function.

The -opioid receptor (MOR) is a G protein-coupled receptor that mediates analgesic, euphoric, and reward effects. Using a bacterial two-hybrid screen, we reported that the carboxyl tail of the rat MOR associates with A20-binding inhibitor of nuclear factor B (ABIN-1). This interaction was confirmed by direct protein-protein binding and coimmunoprecipitation of MOR and ABIN-1 proteins in cell lysates.

Upregulation of Cabin1 During Injury to Renal Tubular Epithelial Cells in Rats.

Introduction: Calcineurin-binding protein 1 (Cabin1) interacts with calcineurin and p53, but its function in renal tubular epithelial cell (RTEC) is unclear. We established 5/6 nephrectomized rats and angiotensin II-induced injury to the RTECs in vitro, to observe the expression of Cabin1 during RTEC injury.

Materials And Methods: Sprague-Dawley rats were sacrificed at 4 and 8 weeks after 5/6 nephrectomy.

The opioid receptor triple agonist DPI-125 produces analgesia with less respiratory depression and reduced abuse liability.

Opioid analgesics remain the first choice for the treatment of moderate to severe pain, but they are also notorious for their respiratory depression and addictive effects. This study focused on the pharmacology of a novel opioid receptor mixed agonist DPI-125 and attempted to elucidate the relationship between the δ-, μ- and κ-receptor potency ratio and respiratory depression and abuse liability. Five diarylmethylpiperazine compounds (DPI-125, DPI-3290, DPI-130, KUST202 and KUST13T02) were selected for this study.

Effects of thienorphine on the contraction of isolated ureter and bladder of guinea pigs.

Opioid analgesics are widely used in moderate to severe pain including renal colic. Morphine is believed to cause spasm of ureter and affect the bladder contractions. Thienorphine is a partial opioid agonist that is a good candidate for the treatment of opioid dependence and pain.

Tacrolimus restores podocyte injury and stabilizes the expression of Cabin1 in 5/6 nephrectomized rats.

Podocyte injury is a vital factor, which induces massive proteinuria. Studies have shown that tacrolimus (TAC) protected podocyte via stabilizing cytoskeleton. Our latest study indicates that calcineurin binding protein 1 (Cabin1) undergoes nuclear translocation during podocytes injury.

The proteins interacting with C-terminal of μ receptor are identified by bacterial two-hybrid system from brain cDNA library in morphine-dependent rats.

Aims: Opioid addiction is associated with long-term adaptive changes in the brain that involve protein expression. The carboxyl-terminal of the μ opioid receptor (MOR-C) is important for receptor signal transduction under opioid treatment. However, the proteins that interact with MOR-C after chronic morphine exposure remain unknown.

Effect of the knockdown of Cabin1 on p53 in glomerular podocyte.

Calcineurin binding protein 1 (Cabin1) is a natural inhibitor of calcineurin (CN). Moreover, Cabin1 retards tumor cell apoptosis by regulating p53. This study was designed to observe the expression of Cabin1 during podocyte injury, as well as its relationship with p53.

Cabin1 localizes in glomerular podocyte and undergoes nuclear translocation during podocyte injury.

Context: Podocyte injury is related to increasing proteinuria and contributes to the progression of kidney disease. Calcineurin binding protein 1 (Cabin1) is a repressor of myocyte enhancer factor 2 (MEF2) and calcineurin-mediated transcription in the immune system. Moreover, Cabin1 interacts with p53 and negatively regulates p53 in tumor cells.

Effects of thienorphine on contraction of the guinea pig sphincter of Oddi, choledochus and gall bladder.

Opioid analgesics are widely believed to cause spasm of the bile duct sphincter and so impede bile flow. Thienorphine is a partial opioid agonist that is a good candidate for the treatment of opioid dependence; however, to date, no studies have reported the effects of thienorphine on the function of the biliary tract. This study examined the in vivo effects of thienorphine on the guinea pig isolated sphincter of Oddi, choledochus and gall bladder and on bile flow.

Multiple mechanisms underlying the long duration of action of thienorphine, a novel partial opioid agonist for the treatment of addiction.

Aims: It is considered that a long-acting therapy would be advantageous in the treatment of addiction. In a search for novel buprenorphine analogues, thienorphine was demonstrated to be an extremely long-acting orally active partial opioid agonist. This study explored the mechanisms underlying the long-lasting effects of thienorphine.

Mas-related G protein-coupled receptor D is coupled to endogenous calcium-activated chloride channel in Xenopus oocytes.

Mas-related G protein-coupled receptor D (MrgD) is expressed almost exclusively in nociceptive primary sensory neurons and the neurons located in stratum granulosum of skin. More and more evidence suggest that MrgD plays an important role in pain sensation and/or transduction. Recent studies have demonstrated that the receptor is also involved in itch sensation in both mouse and human.

Effect of thienorphine on intestinal transit and isolated guinea-pig ileum contraction.

Aim: To evaluate the effect of thienorphine on small intestinal transit in vivo and on guinea-pig ileum (GPI) contraction in vitro.

Methods: The effects of thienorphine on intestinal transit were examined in mice and in isolated GPI. Buprenorphine and morphine served as controls.

Effect of thienorphine on the isolated uterine strips from pregnant rats.

Opioid dependence is a serious worldwide health problem. Buprenorphine was used as an alternative to methadone for the treatment of opioid dependence, especially for pregnant women. Thienorphine was a partial opioid agonist with long-lasting antinociceptive effect and high oral bioavailability compared with its analogue buprenorphine.

CHP1002, a novel andrographolide derivative, inhibits pro-inflammatory inducible nitric oxide synthase and cyclooxygenase-2 expressions in RAW264.7 macrophages via up-regulation of heme oxygenase-1 expression.

Andrographolides, a type of diterpene lactone, are widely known to have anti-inflammatory and anti-oxidative properties. CHP1002, a synthetic derivative of andrographolide, has similar anti-inflammatory action in mouse ear swelling test and rat paw edema test. In the present study, the mechanism of anti-inflammatory effects of CHP1002 was investigated in RAW264.

Effects of thienorphine on release of dopamine and noradrenalin: an in vivo microdialysis study in rats.

Thenorphine is a new potent long-acting partial opioid agonist. In present study, the effect of thienorphine on noradrenalin (NA) in the locus coeruleus (LC) and dopamine (DA) and its metabolites in the nucleus acumbens (NAc) and the striatum were examined in freely moving rats during acute and chronic thienorphine treatment followed by naloxone-precipitated withdrawal using the in vivo microdialysis technique. Acute thienorphine (1.