• Bulletin of the Korean Chemical Society
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• v.31 no.4
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• pp.874-880
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• 2010

A series of 13- and 14-membered cyclic enkephalin analogs based on the moderately $\mu$ selective prototype compound Tyr-C[D-$A_2bu$-Gly-Phe-Leu] 8a were synthesized to investigate the structure-activity relationship. The modifications of sequence were mainly focused on two positions 3 and 5, critical for the selective recognition for $\mu$ and $\delta$ opioid receptors. The substitution of hydrophobic $Leu^5$ with hydrophilic $Asp^5$ derivatives led to Tyr-C[D-$A_2bu$-Gly-Phe-Asp(N-Me)] 7 and Tyr-C[D-Glu-Phe-gPhe-rAsp(O-Me)] 5, the peptides with a large affinity losses at both $\mu$ and $\delta$ receptors. The substitution of $Phe^3$ with $Gly^3$ led to Tyr-C[D-Glu-Gly-gPhe-rLeu] 3 and Tyr-C[D-Glu-Gly-gPhe-D-rLeu] 4, the peptides with large affinity losses at $\mu$ receptors, indicating the critical role of phenyl ring of $Phe^3$ for $\mu$ receptor affinities. One atom reduction of the ring size from 14-membered analogs Tyr-C[D-Glu-Phe-gPhe-(L and D)-rLeu] 6a, 6b to 13-membered analogs Tyr-C[D-Asp-Phe-gPhe-(L and D)-rLeu] 1, 2 reduced the affinity at both $\mu$ and $\delta$ receptors, but increased the potency in the nociceptive assay, indicating the ring constrain is attributed to high nociceptive potency of the analogs. For the influence of D- or L-chirality of $Leu^5$ on the receptor selectivity, regardless of chirality and ring size, all cyclic diastereomers displayed marked $\mu$ selectivity with low potencies at the $\delta$ receptor. The retro-inverso analogs display similar or more active at $\mu$ receptor, but less active at $\delta$ receptor than the parent analogs.

• Journal of Integrative Natural Science
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• v.9 no.3
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• pp.185-189
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• 2016

Urotensin-2 receptor (UTS2R) is the most potent vasoconstrictor and plays a major role in the pathophysiology of various cardiovascular diseases and becomes a potential target for human pharmacotherapy. The crystal structure of Urotension-2 receptor has not yet been resolved. Hence, in the current study homology modelling of UTS2R was done utilizing the crystal structure of human delta opioid receptor as the template. Since the template has low sequence identity, we have incorporated both comparative modelling and threading approach to generate the three dimensional structure. 10 models were generated and validated. The reported models can be used to characterize the critical amino acid residues in the binding site of UTS2R.

• Archives of Pharmacal Research
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• v.28 no.9
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• pp.995-1001
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• 2005

Morphine-induced analgesia has been shown to be antagonized by ginseng total saponins (GTS), which also inhibit the development of analgesic tolerance to and physical dependence on morphine. GTS is involved in both of these processes by inhibiting morphine-6-dehydrogenase, which catalyzes the synthesis of morphinone from morphine, and by increasing the level of hepatic glutathione, which participates in the toxicity response. Thus, the dual actions of ginseng are associated with the detoxification of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contractions in guinea pig ileum (I-L-receptors) and mouse vas deferens $(\delta-receptors)$ are not mediated through opioid receptors, suggesting the involvement of non-opioid mechanisms. GTS also attenuates hyperactivity, reverse tolerance (behavioral sensitization), and conditioned place preference induced by psychotropic agents, such as methamphetamine, cocaine, and morphine. These effects of GTS may be attributed to complex pharmacological actions between dopamine receptors and a serotonergic/adenosine $A_{2A}1\delta-opioid$ receptor complex. Ginsenosides also attenuate the morphine-induced cAMP signaling pathway. Together, the results suggest that GTS may be useful in the prevention and therapy of the behavioral side effects induced by psychotropic agents.

• Journal of Ginseng Research
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• v.14 no.2
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• pp.178-186
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• 1990

The analgesic effect of morphine was antagonized and the development of tolerance was suppressed by the modification of the neurologic function in the animals treated with ginseng saponins The activation of the spinal descending inhibitory systems as well as the supraspinal structures by the administration of morphine was inhibited in the animals treated with ginseng saponine intracerebrally or intrathecally. The development of morphine tolerance and dependence, and the abrupt expression of naloxone inducted abstinence syndrom were also inhibited by ginsenoside Rb1, Rb2, Rg1 and Re. These results suggest that ginsenoside Rbl, Hbs, Rgl and Re are the bioactive components of panax ginseng on the inhibition of the development of morphine tolerance and dependence, and the inhibition of abrupt abstinence sindrome. In addition, further research on the minor components of Pnnnxkinsenl should be investigated. A single or daily treatment with ginseng saponins did not induce any appreciable changes in the brain in level of monoamines at the variolls time intervals and at the various day intervals, respectively. The inhibitory or facilitated effects of ginseng saponins on electrically evoked contractions in guinea pig ileum ($\mu$-receptor) and mouse vats deferens ($\delta$-receptor) were not mediated through opioid receptors. The antagonism of a $\chi$ receptor agonist, U-50, 488H was also not mediated through opioid receptors in the animals treated with ginseng saponins, but mediated through serotonergic mechanisms. Ginseng saponins inhibited morphine 6-dehydrogenase which catalyzed the production of morphinone from morphine, and increased hepatic glutathione contents for the detoxication of morphinone. This result suggests that the dual action of the above plays an important role in the inhibition of the development of morphine tolerance and dependence.

• The Korean Journal of Pain
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• v.23 no.2
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• pp.99-108
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• 2010

Chronic pain is a multifactorial condition with both physical and psychological symptoms, and it affects around 20% of the population in the developed world. In spite of outstanding advances in pain management over the past decades, chronic pain remains a significant problem. This article provides a mechanism- and evidence-based approach to improve the outcome for pharmacologic management of chronic pain. The usual approach to treat mild to moderate pain is to start with a nonopioid analgesic. If this is inadequate, and if there is an element of sleep deprivation, then it is reasonable to add an antidepressant with analgesic qualities. If there is a component of neuropathic pain or fibromyalgia, then a trial with one of the gabapentinoids is appropriate. If these steps are inadequate, then an opioid analgesic may be added. For moderate to severe pain, one would initiate an earlier trial of a long term opioid. Skeletal muscle relaxants and topicals may also be appropriate as single agents or in combination. Meanwhile, the steps of pharmacologic treatments for neuropathic pain include (1) certain antidepressants (tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors), calcium channel ${\alpha}2-{\delta}$ ligands (gabapentin and pregabalin) and topical lidocaine, (2) opioid analgesics and tramadol (for first-line use in selected clinical circumstances) and (3) certain other antidepressant and antiepileptic medications (topical capsaicin, mexiletine, and N-methyl-d-aspartate receptor antagonists). It is essential to have a thorough understanding about the different pain mechanisms of chronic pain and evidence-based multi-mechanistic treatment. It is also essential to increase the individualization of treatment.

• Biomedical Science Letters
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• v.15 no.3
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• pp.199-205
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• 2009

This study was designed to investigate direct effects of [D-$Pen^2$, D-$Pen^5$]-enkephalin, a $\delta$-opioid receptor agonist on the neuronal activity of medial vestibular nuclear (MVN) neurons by whole-cell configuration patch clamp experiments. The spike frequency of MVN neuron was increased to $9.50{\pm}0.55$ (P<0.05) and $10.56{\pm}0.66$ (P<0.05) by 5 and $10{\mu}M$ [D-$Pen^2$, D-$Pen^5$]-enkephalin from the control level of $8.05{\pm}0.55$ spikes/sec, respectively (n=18). The resting membrane potential of the neurons was increased to $-37.86{\pm}0.92$ and $-36.97{\pm}0.97$ (P<0.05) from $-38.74{\pm}1.13\;mV$ by 5 and $10{\mu}M$ [D-$Pen^2$, D-$Pen^5$]-enkephalin, respectively. The amplitude of afterhyperpolarization was decreased to $23.78{\pm}0.65$ and $21.67{\pm}0.89$ (P<0.05) from $23.73{\pm}0.53\;mV$ by 5 and $10{\mu}M$ [D-$Pen^2$, D-$Pen^5$]-enkephalin, respectively. The spike width was changed to $2.22{\pm}0.08$ and $2.24{\pm}0.07$ from $2.20{\pm}0.08\;mV$ by 5 and $10{\mu}M$ [D-$Pen^2$, D-$Pen^5$]-enkephalin, respectively. After pretreatment of naltrindole, a highly selective 8-opioid receptor antagonist, [D-$Pen^2$, D-$Pen^5$]-enkephalin did not change firing rate, resting membrane potential, afterhyperpolarization amplitude, and spike width of MVN neurons. The above experimental results suggest that [D-$Pen^2$, D-$Pen^5$]-enkephalin increases the neuronal activity of MVN neurons via inhibition of calcium-dependent potassium currents underlying the afterhyperpolarization.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2005.11a
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• pp.49-66
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• 2005

Panax ginseng has been useful for the treatment of diverse disease in oriental countries for thousands of years. In addition, a folk medicine prescribed by seven herbal drugs including Panax ginseng has been antinarcotics in the treatment of morphine-dependent patients. Many articles have been reported on these works. Therefore, we review the protective effects of Panax ginseng on the neurotoxicity induced by abuse drugs. Ginseng total saponins (GTS) extracted and isolated by Panax ginseng antagonized Morphine-induced analgesia, and inhibited the development of analgesic tolerance to and physical dependence on morphine. GTS inhibited morphine-6 dehydrogenase, which catalyzes production of mophinone from morphine, and increased hepatic glutathione level responsible to toxicity. Therefore, we hypothesized that these dual actions of ginseng can be associated with the detoxication of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contraction in guinea pig ileum ($\mu$-receptors) and mouse vas deferens($\delta$-receptors) were not mediated through opioid receptors, suggesting non-opioid mechanisms. On the hand, antagonism of U-50,488H ($\kappa$-agonist)-induced antinociception is mediated by serotonergic mechanisms. GTS also inhibited hyperactivity, reverse tolerance (sensitization) and conditioned place preference-induced by psychostimulants such as methamphetamine, cocaine and morphine. On the other hand, GTS reduced the dopamine levels induced by methamphetamine. Moreover, GTS blocked the development of dopamine receptor activation, showing antidopaminergic effect. We suggest that GTS Prevent the methamphetamine-induced striatal dopaminergic neurotoxicity. In addition, Ginsenoside also attenuates morphine-induced cAMP signaling pathway. These results suggested that GTS might be useful for the therapy of the adverse actions of drugs with abuse liability.

• Proceedings of the Ginseng society Conference
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• 2005.11a
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• pp.41-63
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• 2005

Ginseng has been useful for the treatment of diverse disease in oriental countries for thousands of years. In addition, a folk medicine prescribed by seven herbal drugs including Panax ginseng has been antinarcotics in the treatment of morphine-dependent patients. Many articles have been reported on these works. Therefore, we review the protective effects of Panax ginseng on the neurotoxicity induced by abuse drugs. Ginseng total saponins (GTS) extracted and isolated by Panax ginseng antagonized morphine-induced analgesia, and inhibited the development of analgesic tolerance to and physical dependence on morphine. CTS inhibited morphine-6 dehydrogenase, which catalyzes production of mophinone from morphine, and increased hepatic glutathione level responsible to toxicity. Therefore, wehypothesized that these dual actions of ginseng can be associated with the detoxication of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contraction in guinea pig ileum (${\mu}$-receptors) and mouse vas deferens(${\delta}$-receptors) were not mediated through opioid receptors, suggesting non-opioid mechanisms. On the hand, antagonism of U-50,488H (${\kappa}$-agonist)-induced antinociception is mediated by serotonergic mechanisms. GTS also inhibited hyperactivity, reverse tolerance (sensitization) and conditioned place preference-induced by psychostimulants such as methamphetamine, cocaine and morphine. On the other hand, GTS reduced the dopamine levels induced by methamphetamine. Moreover, GTS blocked the development of dopamine receptor activation, showing antidopaminergic effect. We suggest that GTS prevent the methamphetamine-induced striatal dopaminergic neurotoxicity. In addition, Ginsenoside also attenuates morphine-induced CAMP signaling pathway. These results suggested that GTS might be useful for the therapy of the adverse actions of drugs with abuse liability.

• The Korean Journal of Physiology
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• v.21 no.1
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• pp.67-77
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• 1987

Effect of intravenously injected clonidine on the flexion reflex was studied in 15 decerebrated and spinalized cats. The flexion reflex was elicited by electrical stimulation of the tibial nerve or the common peroneal nerve and it was recorded as single unit activity from filaments of the L6 or L7 ventral roots. In order to obtain the late flexion reflex discharges, $A{\delta}$ and C afferent fibers were stimulated with single or train electrical pulses respectively. The flexion reflex, especially the late component, was markedly inhibited after intravenous administration of clonidine. The clonidine-induced inhibition of the flexion reflex was compared before and after treatment of the animals respectively with yohimbine and naloxone. The inhibitory effect on the flexion reflex of clonidine was not altered by naloxone, a ${\mu}-opioid$ receptor blocker, whereas it was completely blocked by yohimbine, an ${\alpha}_2-adrenergic$ antagonist. These results indicate that clonidine inhibits the flexion reflex through excitation of ${\alpha}_2-adrenoceptors$ even at the spinal cord level.

• Proceedings of the Korean Society of Food Science and Nutrition Conference
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• 2001.12a
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• pp.69-73
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• 2001

Two opioid peptides, YPLDL and YPLDLF, were isolated from enzymatic digests of spinach ribulose-1, 5-bisphosphate carboxylase/oxygenase (RuBisCO) and named rubiscolin-5 and -6, respectively. These peptides were selective for delta-receptor and the latter was about 3 times more potent than the former. After oral administration in mice at the dose of 100 mg/kg, rubiscolin-6 showed analgesic activity in tail pinch test. It also stimutated learning performance at the same dose in passive avoidance experiment using step-through apparatus. An immunostimulating peptide, MITLAIPVNKPGR, was isolated from a trypsin digest of soybean protein and named soymetide. Immunostimulating activy of soymetide was mediated by fMLP receptor. Interestingly, after oral administration in rats at a dose of 300 mg/kg (po.), soymetide-4 (MITL) protected alopecia (hair-loss) induced by etoposide, a cancer chemotherapy agent. Stimulation of IL-1 release by the peptide was involved in the mechanism. Ovokinin(2-7), RADHPF, is a vasorelaxing peptide released from ovalbumin by the action of chymotrypsin. It lowered blood pressure of spontaneously hypersensive rats (SHR) after oral administration at a dose of 10 mg/kg. RPLKPW, which was designed by replacing 4 amino acid residues in ovokinin(2-7), exhibited hypotensive activity at a dose of 0.1 mg/kg (po.). This peptides was introduced into 3 homologous sites in soybean beta-conglycinin alpha' subunit by site-directed mutagenesis of the cDNA and expressed in E. coli. The minimum effective dose for hypotensive activity of the genetically modified beta-conglycinin alpha' subunit was 10 mg/kg (po.), which is about 1/200 that of ovalbumin.