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https://www.readbyqxmd.com/read/28212204/1-2-4-dibromophenyl-3-6-6-trimethyl-1-5-6-7-tetrahydro-4h-indazol-4-one-a-novel-opioid-receptor-agonist-with-less-accompanying-gastrointestinal-dysfunction-than-morphine
#1
Po-Kuan Chao, Shau-Hua Ueng, Li-Chin Ou, Teng-Kuang Yeh, Wan-Ting Chang, Hsiao-Fu Chang, Shu-Chun Chen, Pao-Luh Tao, Ping-Yee Law, Horace H Loh, Ming-Fu Cheng, Jian-Ying Chuang, Chiung-Tong Chen, Chuan Shih, Shiu-Hwa Yeh
BACKGROUND: The authors investigated the pharmacology and signaling pathways of the opioid receptors modulated by compound 1, 1-(2,4-dibromophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one. METHODS: In vitro studies of compound 1 were assessed by using a radioligand-binding assay (n = 3), a cyclic adenosine monophosphate assay (n = 3), a β-arrestin assay (n = 3), an internalization assay (n = 3), and an immunohistochemistry (n = 8). In vivo studies of compound 1 were characterized using a tail-flick test (n = 5 to 6), tail-clip test (n = 7), von Frey hair test (n = 5), and charcoal meal test (n = 5)...
February 17, 2017: Anesthesiology
https://www.readbyqxmd.com/read/28190898/synthesis-and-opioid-receptor-binding-of-indium-iii-and-111-in-labeled-macrocyclic-conjugates-of-diprenorphine-novel-ligands-designed-for-imaging-studies-of-peripheral-opioid-receptors
#2
Shefali Srivastava, Emily A Fergason-Cantrell, Roger I Nahas, John R Lever
Radiolabeled diprenorphine (DPN) and analogs are widely used ligands for non-invasive brain imaging of opioid receptors. To develop complementary radioligands optimized for studies of the peripheral opioid receptors, we prepared a pair of hydrophilic DPN derivatives, conjugated to the macrocyclic chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), for complexation with trivalent metals. The non-radioactive indium (III) complexes, tethered to the C6-oxygen position of the DPN scaffold by 6- to 9-atom spacers, displayed high affinities for binding to μ, δ and κ opioid receptors in vitro...
October 6, 2016: Tetrahedron
https://www.readbyqxmd.com/read/28181908/effects-of-endogenous-cardioprotective-mechanisms-on-ischemia-reperfusion-injury
#3
Marcin Kunecki, Wojciech Płazak, Piotr Podolec, Krzysztof S Gołba
Ischemic heart disease have been remarked as a leading cause of morbidity and mortality in adults. Early restoration of cardiac perfusion is necessary to restore perfusion of ischemic heart muscle. Effective revascularization reduce mortality by limiting myocardial necrosis at the acute phase of the cardiac infarction. However, reperfusion may induce a cascade of pathophysiological reactions causing the increase of the infarct area of the myocardium This phenomenon known as ischemia-reperfusion injury is responsible for up to 50% of the final infarct size...
January 10, 2017: Postȩpy Higieny i Medycyny Doświadczalnej
https://www.readbyqxmd.com/read/28167156/eluxadoline-demonstrates-a-lack-of-abuse-potential-in-phase-2-and-3-studies-of-patients-with-irritable-bowel-syndrome-with-diarrhea
#4
Reginald V Fant, Jack E Henningfield, Brooks D Cash, Leonard S Dove, Paul S Covington
BACKGROUND & AIMS: Eluxadoline is approved by the Food and Drug Administration for the treatment of adults with irritable bowel syndrome with diarrhea (IBS-D). Eluxadoline is a locally acting mixed μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist. The abuse potential of eluxadoline was evaluated as part of the Phase 2 and 3 clinical trials assessing the efficacy, safety, and tolerability of the drug. METHODS: One Phase 2 (IBS-2001) and 2 Phase 3 (IBS-3001 and IBS-3002) randomized controlled trials enrolled patients meeting Rome III criteria for IBS-D...
February 3, 2017: Clinical Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28110810/biased-opioid-receptor-ligands-gain-without-pain
#5
Ravi Ranjan, Shubhi Pandey, Arun K Shukla
Kappa opioid receptor (κ-OR) agonists are promising therapeutic candidates for pain and itch; however, they also exhibit the adverse effects of sedation and dysphoria. A recent study has demonstrated that a G protein-biased agonist for κ-OR provides effective pain and itch relief without causing sedation or dysphoria, in animal models.
January 16, 2017: Trends in Endocrinology and Metabolism: TEM
https://www.readbyqxmd.com/read/28107753/role-of-central-opioid-on-the-antinociceptive-effect-of-sulfated-polysaccharide-from-the-red-seaweed-solieria-filiformis-in-induced-temporomandibular-joint-pain
#6
Ianna Wivianne Fernandes Araújo, Hellíada Vasconcelos Chaves, José Mário Pachêco, Danielle Rocha Val, Lorena Vasconcelos Vieira, Rodrigo Santos, Raul Sousa Freitas, Renata Line Rivanor, Valdécio Silvano Monteiro, Juliana Trindade Clemente-Napimoga, Mirna Marques Bezerra, Norma Maria Barros Benevides
This study aimed to investigate the effect of sulfated polysaccharide from red seaweed Solieria filiformis (Fraction F II) in the inflammatory hypernociception in the temporomandibular joint (TMJ) of rats. Male Wistar rats were pretreated (30min) with a subcutaneous injection (s.c.) of vehicle or FII (0.03, 0.3 or 3.0mg/kg) followed by intra-TMJ injection of 1.5% Formalin or 5-hydroxytryptamine (5-HT, 225μg/TMJ). In other set of experiments rats were pretreated (15min) with an intrathecal injection of the non-selective opioid receptors Naloxone, or μ-opioid receptor antagonist CTOP, or δ-opioid receptor Naltridole hydrochloride, or κ-opioid receptor antagonist Nor-Binaltorphimine (Nor-BNI) followed by injection of FII (s...
January 17, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28069442/novel-signaling-of-dynorphin-at-%C3%AE%C2%BA-opioid-receptor-bradykinin-b2-receptor-heterodimers
#7
Bingyuan Ji, Haiqing Liu, Rumin Zhang, Yunlu Jiang, Chunmei Wang, Sheng Li, Jing Chen, Bo Bai
The κ-opioid receptor (KOR) and bradykinin B2 receptor (B2R) are involved in a variety of important physiological processes and share many similar characteristics in terms of their distribution and functions in the nervous system. We first demonstrated the endogenous expression of KOR and B2R in human SH-SY5Y cells and their co-localization on the membrane of human embryonic kidney 293 (HEK293) cells. Bioluminescence and fluorescence resonance energy transfer and the proximity ligation assay were exploited to demonstrate the formation of functional KOR and B2R heteromers in transfected cells...
February 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28065754/mechanisms-involved-in-antinociception-induced-by-a-polysulfated-fraction-from-seaweed-gracilaria-cornea-in-the-temporomandibular-joint-of-rats
#8
Chistiane Oliveira Coura, Hellíada Vasconcelos Chaves, Danielle Rocha do Val, Lorena Vasconcelos Vieira, Felipe Dantas Silveira, Fernanda Maxcynne Lino Dos Santos Lopes, Francisco Isaac Fernandes Gomes, Annyta Fernandes Frota, Ricardo Basto Souza, Juliana Trindade Clemente-Napimoga, Mirna Marques Bezerra, Norma Maria Barros Benevides
Temporomandibular disorder is a common clinical condition involving pain in the temporomandibular joint (TMJ) region. This study assessed the antinociceptive effects of a polysulfated fraction from the red seaweed Gracilaria cornea (Gc-FI) on the formalin-induced TMJ hypernociception in rats and investigated the involvement of different mechanisms. Male Wistar rats were pretreated with injection (sc) of saline or Gc-FI 1h before intra- TMJ injection of formalin to evaluate the nociception. The results showed that pretreatment with Gc-FI significantly reduced formalin-induced nociceptive behavior...
April 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28063353/rationally-designed-benzopyran-fused-isoxazolidines-and-derived-%C3%AE-2-3-3-amino-alcohols-as-potent-analgesics-synthesis-biological-evaluation-and-molecular-docking-analysis
#9
Gagandeep Singh, Gurjit Singh, Rajbir Bhatti, Vivek Gupta, Ajay Mahajan, Palwinder Singh, Mohan Paul Singh Ishar
Based on structure activity analysis of morphine related opiates, we have synthesized some novel benzopyran fused isoxazolidines (2a-e) and derived conformationally constrained β(2,3,3)-amino alcohols (3a-e), which were evaluated in vivo for their anti-nociceptive activity through acetic acid induced writhing test (peripheral) and formalin induced algesia (central). Results showed that, compound 2a possesses significant opioid agonist activity. Further, molecular docking analysis reveals that compound 2a binds to δ-opioid receptor (DOR) with comparatively better D-score than to μ (MOR) and κ (KOR) receptors...
December 28, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28051300/design-and-synthesis-of-potent-and-highly-selective-orexin-1-receptor-antagonists-with-a-morphinan-skeleton-and-their-pharmacologies
#10
Hiroshi Nagase, Naoshi Yamamoto, Masahiro Yata, Sayaka Ohrui, Takahiro Okada, Tsuyoshi Saitoh, Noriki Kutsumura, Yasuyuki Nagumo, Yoko Irukayama-Tomobe, Yukiko Ishikawa, Yasuhiro Ogawa, Shigeto Hirayama, Daisuke Kuroda, Yurie Watanabe, Hiroaki Gouda, Masashi Yanagisawa
Nalfurafine, a κ-selective opioid receptor agonist, unexpectedly showed a selective antagonist activity toward the orexin 1 receptor (OX1R) (Ki = 250 nM). Modification of the 17-amino side chain of the opioid ligand to an arylsulfonyl group and the 6-furan acrylamide chain to 2-pyridyl acrylamide led to compound 71 with improvement of the antagonist activity (OX1R, Ki = 1.36 nM; OX2R, not active) without any detectable affinity for the opioid receptor. The dihydrosulfate salt of 71, freely soluble in water, attenuated the physical dependence of morphine...
February 9, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28049031/the-efficacy-of-dynorphin-fragments-at-the-%C3%AE%C2%BA-%C3%AE-and-%C3%AE-opioid-receptor-in-transfected-hek-cells-and-in-an-animal-model-of-unilateral-peripheral-inflammation
#11
M Morgan, A Heffernan, F Benhabib, S Wagner, A K Hewavitharana, P N Shaw, P J Cabot
Dynorphin 1-17 is an endogenous peptide that is released at sites of inflammation by leukocytes, binding preferentially to κ-opioid receptors (KOP) to mediate nociception. We have previously shown that dynorphin 1-17 is rapidly biotransformed to smaller peptide fragments in inflamed tissue homogenate. This study aimed to determine the efficacy and potency of selected dynorphin fragments produced in an inflamed environment at the KOP, μ and δ-opioid receptors (MOP and DOP respectively) and in a model of inflammatory pain...
December 31, 2016: Peptides
https://www.readbyqxmd.com/read/28033462/the-pharmacological-heterogeneity-of-nepenthone-analogs-in-conferring-highly-selective-and-potent-%C3%AE%C2%BA-opioid-agonistic-activities
#12
Wei Li, Jian-Dong Long, Yuan-Yuan Qian, Yu Long, Xue-Jun Xu, Yu-Jun Wang, Qing Shen, Zuo-Neng Wang, Xi-Cheng Yang, Li Xiao, Hong-Peng Sun, Yu-Long Xu, Yi-Yi Chen, Qiong Xie, Yong-Hui Wang, Li-Ming Shao, Jing-Gen Liu, Zhui-Bai Qiu, Wei Fu
To develop novel analgesics with no side effects or less side effects than traditional opioids is highly demanded to treat opioid receptor mediated pain and addiction issues. Recently, κ-opioid receptor (KOR) has been established as an attractive target, although its selective agonists could bear heterogeneous pharmacological activities. In this study, we designed and synthesized two new series of nepenthone derivatives by inserting a spacer (carbonyl) between 6α,14α-endo-ethenylthebaine and the 7α-phenyl substitution of the skeleton and by substituting the 17-N-methyl group with a cyclopropylmethyl group...
January 19, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/27989510/concurrent-bullatine-a-enhances-morphine-antinociception-and-inhibits-morphine-antinociceptive-tolerance-by-indirect-activation-of-spinal-%C3%AE%C2%BA-opioid-receptors
#13
Qian Huang, Ming-Li Sun, Yuan Chen, Xin-Yan Li, Yong-Xiang Wang
ETHNOPHARMACOLOGICAL RELEVANCE: Bullatine A, a C20-diterpenoid alkaloid and one of the major effective ingredients in Aconiti brachypodi Radix (Xue-shang-yi-zhi-hao), can block pain hypersensitivity in a variety of rodent models through expression of spinal microglial dynorphin A. AIM OF THE STUDY: To assess the interaction between bullatine A and morphine on antinociception in acute nociception and pain hypersensitivity states, with the exogenous synthetic dynorphin A as a comparison MATERIALS AND METHODS: Spinal nerve ligation-induced neuropathic rats and naïve mice were used for assessing the acute and chronic interactions of bullatine A/dynorphin A with morphine...
January 20, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/27958743/synthetic-studies-of-neoclerodane-diterpenes-from-salvia-divinorum-identification-of-a-potent-and-centrally-acting-%C3%AE-opioid-analgesic-with-reduced-abuse-liability
#14
Rachel Saylor Crowley, Andrew P Riley, Alexander M Sherwood, Chad E Groer, Nirajmohan Shivaperumal, Miguel Biscaia, Kelly Paton, Sebastian Schneider, Davide Provasi, Bronwyn M Kivell, Marta Filizola, Thomas E Prisinzano
Opioids are widely used to treat millions suffering from pain, but their analgesic utility is limited due to associated side effects. Herein we report the development and evaluation of a chemical probe exhibiting analgesia and reduced opioid-induced side effects. This compound, kurkinorin (5), is a potent and selective μ-opioid receptor (MOR) agonist (EC50 = 1.2 nM, >8000 μ/κ selectivity). 5 is a biased activator of MOR-induced G-protein signaling over β-arrestin-2 recruitment. Metadynamics simulations of 5's binding to a MOR crystal structure suggest energetically preferred binding modes that differ from crystallographic ligands...
December 22, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27958613/opioid-receptors-in-psoriatic-skin-relationship-with-itch
#15
Piotr Kupczyk, Adam Reich, Marcin Hołysz, Mariusz Gajda, Edyta Wysokińska, Anna Kobuszewska, Dmitry Nevozhay, Beata Nowakowska, Leon Strzadała, Paweł Jagodziński, Jacek C Szepietowski
Psoriasis is an inflammatory immunogenetic skin disease, often accompanied by itch. Opioid receptors are known regulators of itch sensation in the central nervous system. In the brain, μ-opioid receptors may potentiate itch, while activation of κ-opioid receptors may reduce or even alleviate itch; however, the role of opioid receptors in itch perception in the skin is poorly understood. To further elucidate the role of opioid receptors in the neurobiology of psoriatic itch, punch biopsies of non-lesional and lesional skin of patients with psoriasis and healthy controls were studied...
December 13, 2016: Acta Dermato-venereologica
https://www.readbyqxmd.com/read/27922029/safety-of-eluxadoline-in-patients-with-irritable-bowel-syndrome-with-diarrhea
#16
Brooks D Cash, Brian E Lacy, Philip S Schoenfeld, Leonard S Dove, Paul S Covington
OBJECTIVES: Eluxadoline is a mixed μ-opioid receptor (OR) and κ-OR agonist and δ-OR antagonist, approved for the treatment of irritable bowel syndrome with diarrhea (IBS-D). This analysis evaluated the safety and tolerability of eluxadoline 75 and 100 mg twice daily (BID) in one Phase 2 (IBS-2001) and two Phase 3 (IBS-3001 and IBS-3002) studies. METHODS: Adults with IBS-D (Rome III criteria) were randomized to placebo or eluxadoline (75 or 100 mg) BID for 12 (IBS-2001), 26 (IBS-3002), or 52 (IBS-3001) weeks...
December 6, 2016: American Journal of Gastroenterology
https://www.readbyqxmd.com/read/27896372/opioid-receptor-agonists-may-favorably-affect-bone-mechanical-properties-in-rats-with-estrogen-deficiency-induced-osteoporosis
#17
Aleksandra Janas, Joanna Folwarczna
The results of epidemiological, clinical, and in vivo and in vitro experimental studies on the effect of opioid analgesics on bone are inconsistent. The aim of the present study was to investigate the effect of morphine (an agonist of opioid receptors), buprenorphine (a partial μ opioid receptor agonist and κ opioid receptor antagonist), and naloxone (an antagonist of opioid receptors) on the skeletal system of female rats in vivo. The experiments were carried out on 3-month-old Wistar rats, divided into two groups: nonovariectomized (intact; NOVX) rats and ovariectomized (OVX) rats...
February 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/27886263/nicotinic-and-opioid-receptor-regulation-of-striatal-dopamine-d2-receptor-mediated-transmission
#18
Aphroditi A Mamaligas, Yuan Cai, Christopher P Ford
In addition to dopamine neuron firing, cholinergic interneurons (ChIs) regulate dopamine release in the striatum via presynaptic nicotinic receptors (nAChRs) on dopamine axon terminals. Synchronous activity of ChIs is necessary to evoke dopamine release through this pathway. The frequency-dependence of disynaptic nicotinic modulation has led to the hypothesis that nAChRs act as a high-pass filter in the dopaminergic microcircuit. Here, we used optogenetics to selectively stimulate either ChIs or dopamine terminals directly in the striatum...
November 25, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27865836/g-protein-coupled-receptor-kinase-2-upregulation-causes-%C3%AE%C2%BA-opioid-receptor-desensitization-in-diabetic-heart
#19
Xiyao Chen, Shihao Zhao, Yunlong Xia, Zhenyu Xiong, Yueyang Li, Ling Tao, Fuyang Zhang, Xiaoming Wang
Activation of κ-opioid receptor (KOR) ameliorates myocardial ischemia/reperfusion (I/R) injury; however, cardioprotective effects of KOR stimulation disappear in type 1 diabetic subjects with hyperglycemia. The molecular mechanisms underlying this phenomenon remain unknown. Here we found that KOR expression was obviously downregulated and KOR agonism-induced contractile-regulatory and cardioprotective effects were significantly impaired in hearts isolated from streptozotocin (STZ) injection-induced diabetic mice...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27849111/pharmacological-interventions-for-pruritus-in-adult-palliative-care-patients
#20
REVIEW
Waldemar Siemens, Carola Xander, Joerg J Meerpohl, Sabine Buroh, Gerd Antes, Guido Schwarzer, Gerhild Becker
BACKGROUND: This is an update of the original Cochrane review published in 2013 (Issue 6). Pruritus occurs in patients with disparate underlying diseases and is caused by different pathologic mechanisms. In palliative care patients, pruritus is not the most prevalent but is one of the most puzzling symptoms. It can cause considerable discomfort and affects patients' quality of life. OBJECTIVES: To assess the effects of different pharmacological treatments for preventing or treating pruritus in adult palliative care patients...
16, 2016: Cochrane Database of Systematic Reviews
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