• Bulletin of the Korean Chemical Society
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• 제33권1호
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• pp.261-269
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• 2012

The cyclic dimers of enkephalin were isolated as minor components during the solution synthesis of the corresponding cyclic monomers. The ratio of cyclic dimer to monomer was approximately 1:4 from the percent of yields. In the receptor binding assay of two cyclic dimmers, ($Tyr_2-C[D-Glu-Phe-gPhe]_2$ 6, $Tyr_2-C[D-Asp-Phe-gPhe-rLeu]_2$ 8), both analogs exhibited the high preference for ${\delta}$ receptor compared to monocyclic counterparts. In the nociceptive activity, both showed about 5 times less potent than the cyclic monomers. The repeated synthesis of 14-membered cyclic analog, Tyr-C[D-Glu-Phe-gPhe-D-rLeu] 14, which was known as having three distinct cis-trans isomers, gave rise to apparently different conformational analog arousing only trans isomer. In the receptor binding assay, it showed tremendously high selectivity toward ${\mu}$ receptor $({\delta}/{\mu}=160)$.

• International Journal of Oral Biology
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• 제42권1호
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• pp.1-8
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• 2017

In the present study, we investigated the role of peripheral ionotropic receptors in artemin-induced thermal hyperalgesia in the orofacial area. Male Sprague-Dawley rats weighting 230 to 280 g were used in the study. Under anesthesia, a polyethylene tube was implanted in the subcutaneous area of the vibrissa pad, which enabled drug-injection. After subcutaneous injection of artemin, changes in air-puff thresholds and head withdrawal latency time were evaluated. Subcutaneous injection of artemin (0.5 or $1{\mu}g$) produced significant thermal hyperalgesia in a dose-dependent manner. However, subcutaneous injection of artemin showed no effect on air-puff thresholds. IRTX ($4{\mu}g$), a TRPV1 receptor antagonist, D-AP5 (40 or $80{\mu}g$), an NMDA receptor antagonist, or NBQX (20 or $40{\mu}g$), an AMPA receptor antagonist, was injected subcutaneously 10 min prior to the artemin injection. Pretreatment with IRTX and D-AP5 significantly inhibited the artemin-induced thermal hyperalgesia. In contrast, pretreatment with both doses of NBQX showed no effect on artemin-induced thermal hyperalgesia. Moreover, pretreatment with H-89, a PKA inhibitor, and chelerythrine, a PKC inhibitor, decreased the artemin-induced thermal hyperalgesia. These results suggested that artemin-induced thermal hyperalgesia is mediated by the sensitized peripheral TRPV1 and NMDA receptor via activation of protein kinases.

• 약학회지
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• 제45권2호
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• pp.205-213
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• 2001

The dopaminergic receptors were consisted of two distinct subtypes, $D_1$and $D_2$, each having different function. The present study was attempted to investigate the effects of R(-)-2,10,11-trihydroxy-N-n-propylnoraporphine (TNPA), a dopamine $D_2$receptor agonist, on renal function in dog. TNPA (5.0~15.0 $\mu$g/kg), when given into the vein, produced a dose-dependently antidiuresis along with the decrease in osmolar clearance ( $C_{osm}$) and urinary excretion of sodium and potassium ( $E_{Na}$ , and $E_{K}$). It also increased reabsorption rates of sodium and potassium in renal tubules ( $R_{Na}$ , $R_{K}$) without any changes in glomerular filtration rate (GFR), renal plasma flow (RPF) and free water clearance ( $C_{H2o}$). TNPA (0.5~1.5 $\mu$g/kg/min) infused into a renal artery decreased urine flow both in the experimental and the control kidneys. TNPA (1.5~5.0 $\mu$g/kg) administered via the carotid artery also greatly exhibited antidiuresis even at intravenously ineffective doses. Changes of renal function by TNPA given into both the renal artery and the carotid artery were almost the same aspect to those induced by intravenous TNPA. These results obtained from the present study suggest that TNPA produces antidiuresis by increasing the reabsorption rates of electrolytes in renal tubules, mainly distal tubule, through changing of central function.unction.

• The Korean Journal of Physiology and Pharmacology
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• 제8권3호
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• pp.153-159
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• 2004

The interstitial cells of Cajal (ICCs) are the pacemaker cells in gastrointestinal tract and generate electrical rhythmicity in gastrointestinal muscles. Therefore, ICC may be modulated by endogenous agents such as neurotransmitter, hormones, and prostaglandins (PGs). In the present study, we investigated the effects of prostaglandins, especially $PGE_2$, on pacemaker currents in cultured ICCs from murine small intestine by using whole-cell patch clamp techniques. ICCs generated spontaneous slow waves under voltage-clamp conditions and showed a mean amplitude of $-452{\pm}39\;pA$ and frequency of $18{\pm}2$ cycles/min (n=6). Treatments of the cells with $PGE_2$ $(1\;{\mu}M)$ decreased both the frequency and amplitude of the pacemaker currents and increased the resting currents in the outward direction. $PGE_2$ had only inhibitory effects on pacemaker currents and this inhibitory effect was dose-dependent. For characterization of specific membrane EP receptor subtypes, involved in the effects of $PGE_2$ on pacemaker currents in ICCs, EP receptor agonists were used: Butaprost $(1\;{\mu}M)$, $EP_2$ receptor agonist, reduced the spontaneous inward current frequency and amplitude in cultured ICCs (n=5). However sulprostone $(1\;{\mu}M)$, a mixed $EP_1$ and $EP_3$ agonist, had no effects on the frequency, amplitude and resting currents of pacemaker currents (n=5). SQ-22536 (an inhibitor of adenylate cyclase; $100\;{\mu}M$) and ODQ (an inhibitor of guanylate cyclase; $100\;{\mu}M$) had no effects on $PGE_2$ actions of pacemaker currents. These observations indicate that $PGE_2$ alter directly the pacemaker currents in ICCs, and that the $PGE_2$ receptor subtypes involved are the $EP_2$ receptor, independent of cyclic AMP- and GMP-dependent pathway.

• 한국동물학회:학술대회논문집
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• 한국동물학회 1995년도 한국생물과학협회 학술발표대회
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• pp.300.1-300
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• 1995

No Abstract, See Full Text

• 생약학회지
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• 제31권3호
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• pp.273-279
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• 2000

Leukotriene $B_4\;(LTB_4)$ is a pro-inflammatory mediator synthesized in myeloid cells from arachidonic acid. Elevated levels of $LTB_4$ have been found in a number of inflammatory diseases and levels are related to disease activity in some of these. Because $LTB_4$ interacts with cells through specific cell surface receptors, $LTB_4$ receptor blockade is the most specific approach to reduce the pathogenic role of $LTB_4$. In order to find $LTB_4$ receptor antagonist from plants, we screened the $LTB_4$ receptor antagonistic activity of the methanol extract and solvent fractions of herbal drugs. The ability of samples to inhibit specific binding of $[^3H]-LTB_4$ to human peripheral neutrophils was used as assay to evaluate the antagonistic activity of plant materials. Among the tested methanol extracts of herbal drugs, Mori Radicis Cortex, Perillae Semen, Armeniacae Semen and Sophorae subprostratae Radix showed potent inhibitory activity above 70% at the concentration of $100\;{mu}g/ml$. The inhibitory activities of $LTB_4$ binding to human neutrophils were evaluated for several solvent fractions at three different concentrations. Especially, hexane soluble fractions of Anemarrhenae Rhizoma and Embeliae Radix, and ethyl acetate soluble fractions of Aristolochiae Fructus, Magnoliae Cortex and Zingiberis Rhizoma crudus showed moderate activity at $25\;{mu}g/ml$. These fractions were promising candidates for the study of the activity-guided chromatographic purification of active compounds. Silica gel column chromatography of hexane soluble fractions of Anemarrhenae Rhizoma and Embeliae Radix gave very active sub-fractions, AA-4 and ES-4, and their inhibition activities of $LTB_4$ binding to human neutrophil at $30\;{mu}g/ml$ were 78% and 62%, respectively. From these results we could anticipate new $LTB_4$ receptor antagonist from herbal drugs, and the block of $LTB_4$ effects may provide beneficial in neutrophil mediated diseases such as inflammation and bronchial asthma.

• The Korean Journal of Physiology and Pharmacology
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• 제2권2호
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• pp.147-154
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• 1998

It was attempted to clarify the participation of $K^+-channels$ in the post-receptor mechanisms of the muscarinic and $A_1-adenosine$ receptor- mediated control of acetylcholine (ACh) release in the present study. Slices from the rat hippocampus were equilibrated with $[^3H]$choline and the release of the labelled products was evoked by electrical stimulation (3 Hz, 5 V/cm, 2 ms, rectangular pulses), and the influence of various agents on the evoked tritium-outflow was investigated. Oxotremorine (Oxo, $0.1{\sim}10\;{\mu}M$), a muscarinic agonist, and $N^6-cyclopentyladenosine$ (CPA, $1{\sim}30\;{\mu}M$), a specific $A_1-adenosine$ agonist, decreased the ACh release in a dose-dependent manner, without affecting the basal rate of release. 4-aminopyridine (4AP), a specific A-type $K^+-channel$ blocker ($1{\sim}100\;{\mu}M$), increased the evoked ACh release in a dose-related fashion, and the basal rate of release is increased by 3 and $100\;{\mu}M$. Tetraethylammonium (TEA), a non-specific $K^+-channel$ blocker ($0.1{\sim}10\;{\mu}M$), increased the evoked ACh release in a dose-dependent manner without affecting the basal release. The effects of Oxo and CPA were not affected by $3\;{\mu}M$ 4AP co-treatment, but 10 mM TEA significantly inhibited the effects of Oxo and CPA. 4AP ($10\;{\mu}M$)- and TEA (10 mM)-induced increments of evoked ACh release were completely abolished in Ca^{2+}-free$ medium, but these were recoverd in low Ca^{2+}$ medium. And the effects of $K^+-channel$ blockers in low Ca^{2+}$ medium were inhibited by $Mg^{2+}$ (4 mM) and abolished by $0.3\;{\mu}M$ tetrodotoxin (TTX). These results suggest that the changes in TEA-sensitive potassium channel permeability and the consequent limitation of Ca^{2+}$ influx are partly involved in the presynaptic modulation of the evoked ACh-release by muscarinic and $A_1-adenosine$ receptors of the rat hippocampus.

• International Journal of Oral Biology
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• 제33권4호
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• pp.217-221
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• 2008

Bicuculline is one of the most commonly used $GABA_A$ receptor antagonists in electrophysiological research. Because of its poor water solubility, bicuculline quaternary ammonium salts such as bicuculline methiodide (BMI) and bicuculline methbromide are preferred. However, a number of studies have shown that BMI has non-$GABA_A$ receptor-mediated effects. The substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) is implicated in the processing of nociceptive signaling. In this study, we investigated whether BMI has non-GABA receptor-mediated activity in Vc SG neurons using a whole cell patch clamp technique. SG neurons were depolarized by application of BMI ($20{\mu}M$) using a high $Cl^-$ pipette solution. GABA ($30-100{\mu}M$) also induced membrane depolarization of SG neuron. Although BMI is known to be a $GABA_A$ receptor antagonist, GABA-induced membrane depolarization was enhanced by co-application with BMI. However, free base bicuculline (fBIC) and picrotoxin (PTX), a $GABA_A$ and $GABA_C$ receptor antagonist, blocked the GABA-induced response. Furthermore, BMI-induced membrane depolarization persisted in the presence of PTX or an antagonist cocktail consisting of tetrodotoxin ($Na^+$ channel blocker), AP-5 (NMDA receptor antagonist), CNQX (non-NMDA receptor antagonist), and strychnine (glycine receptor antagonist). Thus BMI induces membrane depolarization by directly acting on postsynaptic Vc SG neurons in a manner which is independent of $GABA_A$ receptors. These results suggest that other unknown mechanisms may be involved in BMI-induced membrane depolarization.

• 약학회지
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• 제43권5호
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• pp.642-651
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• 1999

Nonsedating antihistamines do net cause sedation in therapeutic doses because these drugs hardly cross the blood-brain barrier. Since most of the peripheral side dffects of conventional antihistamines are related to their muscarinic receptor blocking action, the present study was performed to investigate whether nonsedating antihistamines interact with the muscarinic receptors and discriminate the muscarinic receptor subtypes in the rat cerebral microsomal fraction which containes both $M_1,{\;}M_2,{\;}M_3{\;}and{\;}M_4$ receptors. Five nonsedating antihistamines at high concentrations inhibited [$^3H$]QNB binding to the muscarinic receptor in a dose-dependent manner. The inhibition curves of these drugs except loratadine which showed positive cooperativity (nH=1.55) were steep (nH=1), indicating interaction with a single homogenous population of the binding sites. Astemizole, clemizole and mequitazine increased the $K_D$ value for [$^3H$]QNB without affecting the binding site concentrations, and this increase in the $K_D$ value resulted from the ability of these drugs to slow [$^3H$]QNB-receptor association. The Ki values of astemizole, clemizole and mequitazine for the inhibition for the inhibition of [$^3H$]QNB binding to muscarinic receptor were 0.58, 5.99 and $0.007{\;}{\mu}M$, respectively. However, loratadine and terfenadine inhibited noncompetitively [$^3H$]QNB binding with the normalized $IC_50$ value of about $2{\;}{\mu}M$. These results demonstrate that; 1) astemizole, clemizole and mequitazine interact directly with the muscarinic receptor at high concentrations; 2) muscarinic receptor blocking potency of these drugs varies widely among drugs; 3) these drugs do not discriminate between muscarinic receptor subtypes.

• The Korean Journal of Pain
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• 제30권2호
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• pp.98-103
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• 2017

Background: The root of Peucedanum japonicum Thunb., a perennial herb found in Japan, the Philippines, China, and Korea, is used as an analgesic. In a previous study, sec-O-glucosylhamaudol (SOG) showed an analgesic effect. This study was performed to examine the antinociceptive effect of intrathecal SOG in the formalin test. Methods: Male Sprague-Dawley rats were implanted with an intrathecal catheter. Rats were randomly treated with a vehicle and SOG ($10{\mu}g$, $30{\mu}g$, $60{\mu}g$, and $100{\mu}g$) before formalin injection. Five percent formalin was injected into the hind-paw, and a biphasic reaction followed, consisting of flinching and licking behaviors (phase 1, 0-10 min; phase 2, 10-60 min). Naloxone was injected 10 min before administration of SOG $100{\mu}g$ to evaluate the involvement of SOG with an opioid receptor. Dose-responsiveness and ED50 values were calculated. Results: Intrathecal SOG showed a significant reduction of the flinching responses at both phases in a dose-dependent manner. Significant effects were showed from the dose of $30{\mu}g$ and maximum effects were achieved at a dose of $100{\mu}g$ in both phases. The ED50 value (95% confidence intervals) of intrathecal SOG was 30.3 $(25.8-35.5){\mu}g$ during phase 1, and 48.0 (41.4-55.7) during phase 2. The antinociceptive effects of SOG ($100{\mu}g$) were significantly reverted at both phases of the formalin test by naloxone. Conclusions: These results demonstrate that intrathecal SOG has a very strong antinociceptive effect in the formalin test and it seems the effect is related to an opioid receptor.