• Title/Summary/Keyword: NK1-receptor antagonist

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Structure-Antagonistic Activity Relationships of an NK-2 Tachykinin Receptor Antagonist, L-659,877 and Its Analogues

  • Ha, Jong-Myung;Shin, Song-Yub;Hong, Hea-Nam;Suh, Duk-Joon;Jang, Tae-Sik;Kang, Shin-Won;Kuean, Sun-Jin;Ha, Bae-Jin
    • BMB Reports
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    • v.29 no.5
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    • pp.429-435
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    • 1996
  • To investigate the structure-antagonistic relationship of the cyclohexapeptide L-659,877, a selective NK-2 tachykinin receptor antagonist, seven analogues were chemically synthesized by a solid phase method. The agonistic and antagonistic activities of the analogues were evaluated by contraction assay using the smooth muscle of guinea pig trachea (GPT) containing the NK-2 receptor. It was shown that the aromatic ring of Phe at position 3 and the sulfur group of Met at position 6 in L-659,877 were essential for binding to the NK-2 receptor. Decrease in antagonistic activity of L-659,877 caused by substituting Leu for Nle at position 5 indicates that the ${\gamma}$ methyl group and side chain length of Leu plays an important role in its antagonistic action. Although the activity was slightly lower than L-659,877, cyclo $[{\beta}Ala^{8}]NKA(4-10)$ (analogue 1) showed potential antagonistic activity for the NK-2 receptor. It was confirmed that the expansion of the ring in L-659,877 by substitution of ${\beta}Ala$ for Gly at position 4 stabilized its conformation monitored by CD spectra. The results suggest that analogue 1 can be used as a new leader compound to design a more powerful, selective, and stable NK-2 receptor antagonist.

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Nonadrenergic Noncholinergic Nerve-mediated Contraction of the Longitudinal Muscle of Rat Ileum (랫드 회장 종주근의 비아드레날린 비콜린성 신경에 의한 수축반응)

  • Kim, Tae-wan;La, Jun-ho;Sung, Tae-sik;Kang, Jung-woo;Yang, Il-suk;Han, Ho-jae
    • Korean Journal of Veterinary Research
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    • v.43 no.3
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    • pp.405-414
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    • 2003
  • The purpose of this study was to assess the role of tachykinins (TK) in mediating nonadrenergic noncholinergic (NANC) contractions produced by electrical field stimulation (EFS) in the longitudinal muscle of the rat ileum. In the presence of atropine ($1{\mu}M$), guanethidine ($5{\mu}M$), and L-nitroarginine (L-NNA, $200{\mu}M$), EFS (0.5ms pulse duration, 120 V, 1-20 Hz for 2 min) produced a frequency-dependent slowly-developing tonic contraction with superimposed phasic contractions ('on'-contraction) followed by off slowly-decreasing tonic and superimposed phasic contractions ('off'-contraction) of mucosa-free longitudinal oriented muscle strip. These EFS induced responses were blocked by tetrotoxin. $NK_1$ receptor selective antagonist L-732,138 strongly inhibited the EFS-induced excitatory responses. However $NK_2$ receptor selective antagonist, GR 159897 and $NK_3$ receptor selective antagonist SB 222200 did not significantly inhibited the responses. $NK_1$ receptor selective agonist [$Sar^9$,$Met(O_2)^{11}$] Substance P and $NK_2$ receptor selective agonist [${\beta}-Ala^8$]-neurokinin A (4-10) induced tonic contraction with superimposed phasic contractions of longitudinal oriented muscle strip and almost blocked by selective antagonist L-732,138 and GR 159897, respectively. But $NK_3$ receptor selective agonist senktide did not showed any effect. Nifedipine ($1{\mu}M$) abolished the contraction produced either by EFS or by the TK receptor agonists [$Sar^9$,$Met(O_2)^{11}$] Substance P or [${\beta}-Ala^8$]-neurokinin A (4-10). It is concluded that, in the longitudinal muscle of rat ileum, both $NK_1$ and $NK_2$ receptors modulated the responses to exogenous tachykinins, whereas $NK_1$ is mainly involved in NANC neuromuscular contraction.

Anti-nociceptive effects of dual neuropeptide antagonist therapy in mouse model of neuropathic and inflammatory pain

  • Kim, Min Su;Kim, Bo Yeon;Saghetlians, Allen;Zhang, Xiang;Okida, Takuya;Kim, So Yeon
    • The Korean Journal of Pain
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    • v.35 no.2
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    • pp.173-182
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    • 2022
  • Background: Neurokinin-1 (NK1) and calcitonin gene-related peptide (CGRP) play a vital role in pain pathogenesis, and these proteins' antagonists have attracted attention as promising pharmaceutical candidates. The authors investigated the anti-nociceptive effect of co-administration of the CGRP antagonist and an NK1 antagonist on pain models compared to conventional single regimens. Methods: C57Bl/6J mice underwent sciatic nerve ligation for the neuropathic pain model and were injected with 4% formalin into the hind paw for the inflammatory pain model. Each model was divided into four groups: vehicle, NK1 antagonist, CGRP antagonist, and combination treatment groups. The NK1 antagonist aprepitant (BIBN4096, 1 mg/kg) or the CGRP antagonist olcegepant (MK-0869, 10 mg/kg) was injected intraperitoneally. Mechanical allodynia, thermal hypersensitivity, and anxiety-related behaviors were assessed using the von Frey, hot plate, and elevated plus-maze tests. The flinching and licking responses were also evaluated after formalin injection. Results: Co-administration of aprepitant and olcegepant more significantly alleviated pain behaviors than administration of single agents or vehicle, increasing the mechanical threshold and improving the response latency. Anxiety-related behaviors were also markedly improved after dual treatment compared with either naive mice or the neuropathic pain model in the dual treatment group. Flinching frequency and licking response after formalin injection decreased significantly in the dual treatment group. Isobolographic analysis showed a meaningful additive effect between the two compounds. Conclusions: A combination pharmacological therapy comprised of multiple neuropeptide antagonists could be a more effective therapeutic strategy for alleviating neuropathic or inflammatory pain.

Excitatory effect of KR-25018 and capsaicin on the isolated guinea pig bronchi

  • 정이숙;신화섭;박노상;문창현;조태순
    • Proceedings of the Korean Society of Applied Pharmacology
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    • 1996.04a
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    • pp.252-252
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    • 1996
  • We Investigated the peripheral excitatory effect of capsaicin and KR-25018, a newly synthesized capsaicin derivative which was demonstrated to have a potent analgesic activity. KR-25018 and capsaicin were found to be both potent efficacious contractors of isolated guinea pig bronchial smooth muscle. KR-25018 was equipotent with capsaicin and [Sar$\^$9/,Met(O$_2$)$\^$11/]-substance P, 10-fold more potent than histamine and 10-fold less potent than (${\beta}$ -Ala$\^$8/)-neurokinin A(4-10), and their -log(M)EC$\_$50/ values were 6.94${\pm}$0.08, 6.86${\pm}$0.05, 6.96${\pm}$0.07, 5.64${\pm}$0.04, 7.96${\pm}$0.02, respectively. Contractile responses to KR-25018 and capsaicin were potentiated by phosphoramidon (1 ${\mu}$M), an inhibitor of neuropeptide-inactivating endopeptidase, but completely abolished in a calcium-free medium. These responses to KR-25018 and capsaicin were unaffected by the NK-1 antagonist CP96345 (1${\mu}$M), partially inhibited by the NK-2 antagonist SR48968 (1 ${\mu}$M) but almost completely abolished by a combination of the antagonists. A vanilloid receptor antagonist capsazepine competitively antagonized the responses to both KR-25018 and capsaicin (pA$_2$: aganst KR-25018, 5.98${\pm}$0.47; against capsaicin, 5.80${\pm}$0.31), and a capsaicin-sensitive cation channel antagonist ruthenium red caused significant reduction in the maximum responses to KR-25018 and capsaicin (pD'$_2$: against KR-25018, 4.61${\pm}$0.33; against capsaicin 4.96${\pm}$0.21). In conclusion, the present results suggest that KR-25018 and cpasaicin act on the same vanilloid receptor inducing the influx of calcium through ruthenium red-sensitive cation channel and produce contractile responses via the release of tachykinins that act on both NK-1 and NK-2 receptor subtypes.

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Effects of Tachykinins on Intestinal Smooth Muscle of Nile tilapia(Oreochromis niloticus) and Israel carp(Cyprinus carpio) (나일틸라피아(Oreochromis niloticus)와 이스라엘잉어(Cyprinus carpio)의 장관 평활근의 수축활성에 미치는 Tachykinin류의 영향)

  • Kim, Eun-Hee;Seo, Jung-Soo;Huh, Min-Do;Park, Nam-Gyu;Lee, Hyung-Ho;Chung, Joon-Ki
    • Journal of fish pathology
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    • v.14 no.1
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    • pp.46-53
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    • 2001
  • The present study was undertaken to investigate and compare the effect and mode of action of tachykinins on isolated strip preparations of the intestinal smooth muscle from the nile tilapia, Oreochromis niloticus and the Israel carp, Cyprinus carpio. Both of neurokinin 1(NK-1) receptor agonist, substance P(SP) and neurokinin 2(NK-2) receptor agonist, neurokinin A(NKA) caused concentration-dependent contractions of intestinal smooth muscle in the nile tilapia and the israel carp. The efficiency and potency of these agonists varied between two fish species. In the nile tilapia intestine, the efficiency and potency of SP were greater than those of NKA. However, the efficiency and potency of SP were similar to those of NKA. In the nile tilapia intestine and the israel carp intestine, the contractile responses of SP and NKA were noncompetitively antagonized by NK-1 receptor antagonist, L-732, 138 but unaffected by NK-2 receptor antagonist, MDL 29913. In addition, SP-induced contractions in the both of preparation were significantly inhibited by muscarinic antagonist, atropine($5{\times}10^{-7}$M) and ganglionic inhibitor, tetrodotoxin($2{\times}10^{-7}$M) but NKA-induced contractions were unaffected by those. These results indicate that two tachykinin agonists, SP and NKA predominately modulate the mechanical activity of isolated preparation from the nile tilapia and the israle carp directly through the activation of NK-1 receptor on the intestinal smooth muscle cells, but in the case of SP action, the indirect action through activation of cholinergic nerve terminals seems to be also implicated.

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Conformation of cyclo-[Gln-Trp-Phe- $\beta$Ala-Leu-Met], a NK-2 Tachykinin Receptor Antagonist (NK-2의 Antagonist인 cyclo-[Gln-Trp-Phe- $\beta$Ala-Leu-Met]의 형태에 관한 연구)

  • Ha, Jong Myung
    • Journal of the Korean Chemical Society
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    • v.43 no.5
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    • pp.540-546
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    • 1999
  • Solution conformation of cyclo-($Gln^1-Trp^2-Phe^3-{\beta}Ala^4-Leu^5-Met^6$), new NK-2 antagonist in dimethyl sulfoxide solution, has been determined by the use of two-dimensional nuclear magnetic resonance spectroscopy combined with simulated annealing calculations. The peptide exhibited converged structures with the atomic root-mean-square difference for the backbone atoms ($N,\;C^{\alpha},\;C'$) of all residues being 0.02${\AA}$ in the 25 annealed structures. The analysis of the structures indicated that the cyclic peptide has three intramolecular hydrogen bonds between $Met^6NH$ and ${\beta}Ala^4CO$, ${\beta}Ala^4NH$ and $Met^6CO$, $Phe^3NH$ and $Met^6CO$, and contain a type-I ${\beta}$-turn with Gln and Trp and ${\gamma}$-turn with Leu. The addition of an extra methylene group to Gly, i.e. P-Ala residue, may relax some unfavorable restraints in the cyclic backbone structure, hence enabling an additional hydrogen bond, which results in stabilizing one conformation.

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Expression of Nociceptin within Dura Mater in Response to Electrical Trigeminal Ganglion Stimulation in Rats

  • Kim, Jeong-Hee;Lee, Won-Suk
    • Biomedical Science Letters
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    • v.11 no.3
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    • pp.375-382
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    • 2005
  • This study aimed to investigate whether nociceptin is implicated in the, trigeminovascular responses to electrical stimulation of trigeminal ganglion in rats. An open cranial window was prepared on the right parietal bone of male Sprague-Dawley rats. Trigeminovascular system was stimulated by electrical stimulation of trigeminal ganglion (ETS; 5ms, 5Hz, 3V). Neonatal capsaicin treatment was performed with subcutaneous administration of capsaicin (50mg/kg) within the first 24 hours after birth. Changes in regional cerebral blood flow were continuously measured through the cranial window by laser-Doppler flowmetry, and the expression of nociceptin-like immunoreactivity was determined by immunohistochemistry. ETS caused increases in regional blood flow of pial arteriole in a voltage-dependent manner. ETS markedly and voltage-dependently increased the expression of nociceptin-like immunoreactivity in dura mater ipsilateral rather than contralateral to ETS. The nociceptin-like immunoreactivity was markedly reduced by pretreatments with calcitonin gene-related peptide(8-37) ($CGRP_{8-37},\;a\;CGRP_1$ receptor antagonist), L-733060 (a $NK_1$ receptor antagonist), and $[Nphe^1]$ nociceptin(1-13)$NH_2$ (a selective and competitive nociceptin receptor antagonist) as well as by neonatal capsaicin treatment. These results suggest that the electrical stimulation of trigeminal ganglion causes prominent expression of nociceptin within dura mater, in which not only neuropeptides inducing substance P and CGRP but also nociceptin are implicated in the trigeminovascular responses to electrical trigeminal ganglion stimulation.

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Effects of FK224, a $NK_1$ and $NK_2$ Receptor Antagonist, on Plasma Extravasation of Neurogenic Inflammation in Rat Airways (미주 신경의 전기적 자극으로 유발된 백서의 기도내 혈장 유출에 대한 FK224의 효과)

  • Shim, Jae-Jeong;Lee, Sang-Yeub;Lee, Sang-Hwa;Park, Sang-Myun;Seo, Jeong-Kyung;Cho, Jae-Yun;In, Kwang-Ho;Yoo, Se-Hwa;Kang, Kyung-Ho
    • Tuberculosis and Respiratory Diseases
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    • v.42 no.5
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    • pp.744-751
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    • 1995
  • Background: Asthma is an inflammatory disease because there are many inflammatory changes in the asthmatic airways. Axon reflex mechanisms may be involved in the pathogenesis of asthma. Sensory neuropeptides are involved in this inflammation, which is defined as neurogenic inflammation. Substance p, neurokinin A, and neurokinin B may be main neuropeptides of neurogenic inflammation in airways. These tachykinins act on neurokinin receptors. Three types of neurokinin receptors, such as $NK_1$, $NK_2$, and $NK_3$, are currently recognized, at which substance p, neurokinin A, and neurokinin B may be the most relevant natural agonist of neurogenic inflammation in airways. The receptor subtypes present in several tissues have been characterized on the basis of differential sensitivity to substance p, neurokinin A, and neurokinin B. Plasma extravasation and vasodilation are induced by substance p more potently than by neurokinin A, indicating NK1 receptors on endothelial cells mediate the response. But airway contraction is induced by neurokinin A more potently than by substance P, indicating the $NK_2$ receptors in airway smooth muscles. These receptors are used to evaluate the pathogenesis of brochial asthma. FK224 was identified from the fermentation products of Streptomyces violaceoniger. FK224 is a dual antagonist of both $NK_1$ and $NK_2$ receptors. Purpose: For a study of pathogenesis of bronchial asthma, the effect of FK224 on plasma extravasation induced by vagal NANC electrical stimulation was evaluated in rat airway. Method: Male Sprague-Dawley rats weighing 180~450gm were anesthetized by i.p. injection of urethane. Plasma extravasation was induced by electrical stimulation of cervical vagus NANC nerves with 5Hz, 1mA, and 5V for 2 minutes(NANC2 group) and for sham operation without nerve stimulation(control group). To evaluate the effect of FK224 on plasma extravasation in neurogenic inflammation, FK224(1mg/kg, Fujisawa Pharmaceutical Co., dissolved in dimethylsulphoxide; DMSO, Sigma Co.) was injected 1 min before nerve stimulation(FK224 group). To assess plasma exudation, Evans blue dye(20mg/kg, dissolved in saline) was used as a plasma marker and was injected before nerve stimulation. After removal of intravascular dye, the evans blue dye in the tissue was extracted in formamide($37^{\circ}C$, 24h) and quantified spectrophotometrically by measuring dye absorbance at 629nm wavelength. Tissue dye content was expressed as ng of dye per mg of wet weight tissue. The amount of plasma extravasation was measured on the part of airways in each groups. Results: 1) Vagus nerve(NANC) stimulation significantly increased plasma leakage in trachea, main bronchus, and peripheral bronchus compared with control group, $14.1{\pm}1.6$ to $49.7{\pm}2.5$, $17.5{\pm}2.0$ to $38.7{\pm}2.8$, and $12.7{\pm}2.2$ to $19.1{\pm}1.6ng$ of dye per mg of tissue(mean ${\pm}$ SE), respectively(p<0.05). But there was not significantly changed in lung parenchyma(p>0.05) 2) FK224 had significant inhibitory effect upon vagal nerve stimulation-induced airway plasma leakage in any airway tissues of rat,such as trachea, main bronchus, and peripheral bronchus compared with vagus nerve stimulation group, 49%, 58%, and 70%, respectively(p<0.05). Inhibitory effect of FK224 on airway plasma leakage in neurogenic inflammation was revealed the more significant in peripheral bronchus, but no significant in lung parenchyma. Conclusion: These results suggest that FK224 is a selective NK receptor antagonist which effectively inhibits airway plasma leakage induced by the endogenous neurotransmitters relased by neurogenic inflammation in rat airway. Tachykinin receptor antagonists may be useful in the treatment of brochial asthma.

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Efficacy and Safety of Neurokinin-1 Receptor Antagonists for Prevention of Chemotherapy-Induced Nausea and Vomiting: Systematic Review and Meta-analysis of Randomized Controlled Trials

  • Yuan, Dong-Mei;Li, Qian;Zhang, Qin;Xiao, Xin-Wu;Yao, Yan-Wen;Zhang, Yan;Lv, Yan-Ling;Liu, Hong-Bin;Lv, Tang-Feng;Song, Yong
    • Asian Pacific Journal of Cancer Prevention
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    • v.17 no.4
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    • pp.1661-1675
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    • 2016
  • Objectives: Can addition of neurokinin-1 receptor antagonists (NK1-RAs) be considered as an ideal strategy for the prevention of chemotherapy-induced nausea and vomiting (CINV)? Researchers differ on this question. Materials and Methods: Electronic databases were searched for randomized control trials (RCTs) that evaluated the effectiveness and safety of NK1-RAs in preventing CINV. The primary end point was complete response (CR) in the acute, delayed, and overall phases after chemotherapy. Subgroup analyses evaluated the types of NK1-RAs, routines of administration, types of malignancies, regimens used in combination with NK1-RAs, and age of patients included in the studies. The incidences of different types of adverse events were also extracted to estimate the safety of NK1-RAs. Results: A total of 38 RCTs involving 13,923 patients were identified. The CR rate of patients receiving NK-RAs was significantly higher than patients in the control groups during overall phase (70.8% vs 56.0%, P<0.001), acute phase (85.1% vs 79.6%, P<0.001), and delayed phase (71.4% vs 58.2%, P<0.001). There were three studies including patients of children or adolescents, the CR rate was also significantly higher in the treatment group (overall phase: OR=2.807, P<0.001; acute phase: OR=2.863, P =0.012; delayed phase: OR=2.417, P<0.001). For all the other outcomes, patients in the NK1-RAs groups showed improvements compared to the control groups (incidence of nausea: 45.2% vs 45.9%, P<0.001; occurrence of vomiting: 22.6% vs 38.9%, P<0.001; usage of rescue drugs: 23.5% vs 34.1%, P<0.001). The pooled side effects from NK1-RAs did not significantly differ from previous reports and the toxicity rates in patients less than eighteen years old also did not diff between the two groups (P=0.497). However, we found that constipation and insomnia were more common in the patients of control groups, whereas diarrhea and hiccups were more frequently detected in patients receiving NK1-RAs. Conclusions: NK1-RAs improved the CR rate of CINV. They are effective for both adults and children. The use of NK1-RAs might be associated with the appearance of diarrhea and hiccups, while decreasing the possibility of constipation and insomnia.

The Effect of Aprepitant Regimen on the Prevention of High-Dose Cisplatin-Induced Nausea and Vomiting (Aprepitant Regimen의 고용량 Cisplatin 유발 오심 및 구토 예방 효과)

  • Park, Su-Jin;Choi, Ji-Seon;Ahn, Jin-Seok;Shin, Ka-Young;Min, Kyoung-A;Chung, Seon-Young;In, Yong-Won;Sohn, Kie-Ho
    • Korean Journal of Clinical Pharmacy
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    • v.20 no.1
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    • pp.17-23
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    • 2010
  • Aprepitant is a substance P/neurokinin-1 (NK1)-receptor antagonist that was approved in 2003 for prevention of CINV. In addition, updated anti-emetic guidelines that include the aprepitant regimen have been published by NCCN and ASCO. However there is scarce clinical data in Korea. The prospective study was performed to evaluate the prevention of high dose cisplatin induced nausea and vomiting in all patients who started high-dose cisplatin-based chemotherapy at our hospital. We checked the nausea severity and vomiting episodes by calling patients within 4 to 5 days after chemotherapy. The retrospective study was performed to compare the prevention of CINV in solid tumor patients who switched their anti-emesis regimen from the standard regimen to the aprepitant regimen. In aprepitant regimen, aprepitant was added to the same anti-emetic regimen used during previous cycles. We checked the nausea, vomiting grades and adverse events in electronic medical records (EMR). In prospective study, 195 patients were included in the analysis. 88.2% of patients achieved a complete response (no emesis and no rescue therapy). In retrospective study, 54 patients were reviewed. With aprepitant regimen, nausea and vomiting grades were improved in 22 patients (40.7%) and in 9 patients (16.7%), respectively. Compared with standard regimen, addition of aprepitant provided superior prevention against CINV in Korean patients receiving highly emetogenic cisplatin-based chemotherapy. Moreover, aprepitant significantly prevented CINV in patients who received the standard regimen to prevent CINV in previous chemotherapy cycles.