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Article ; Online: ASP8477, a fatty acid amide hydrolase inhibitor, exerts analgesic effects in rat models of neuropathic and dysfunctional pain.

Kiso, Tetsuo / Watabiki, Tomonari / Sekizawa, Toshihiro

2020 Volume 881, Page(s) 173194

Abstract: Exogenous cannabinoid receptor agonists are clinically effective for treating chronic pain but frequently cause side effects in the central nervous system. Fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme for anandamide, an endogenous ... ...

Abstract	Exogenous cannabinoid receptor agonists are clinically effective for treating chronic pain but frequently cause side effects in the central nervous system. Fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme for anandamide, an endogenous cannabinoid agonist. 3-Pyridyl 4-(phenylcarbamoyl)piperidine-1-carboxylate (ASP8477) is a potent and selective FAAH inhibitor that is orally active and able to increase the brain anandamide level and is effective in rat models of neuropathic and osteoarthritis pain without causing motor coordination deficits. In the present study, we examined the pharmacokinetics and pharmacodynamics, analgesic spectrum in pain models, and the anti-nociceptive mechanism of ASP8477. Single and four-week repeated oral administration of ASP8477 ameliorated mechanical allodynia in spinal nerve ligation rats with similar improvement rates. Further, single oral administration of ASP8477 improved thermal hyperalgesia and cold allodynia in chronic constriction nerve injury rats. ASP8477 also restored muscle pressure thresholds in reserpine-induced myalgia rats. This analgesic effect of ASP8477 persisted for at least 4 h, consistent with the inhibitory effect observed in an ex vivo study using rat brain as well as the increasing effect on oleoylethanolamide and palmitoylethanolamide levels but not the ASP8477 concentration in rat brain. ASP8477 also improved α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-, N-methyl-D-aspartic acid (NMDA)-, prostaglandin E
MeSH term(s)	Amides/metabolism ; Amidohydrolases/antagonists & inhibitors ; Amidohydrolases/metabolism ; Analgesics/pharmacokinetics ; Analgesics/pharmacology ; Animals ; Behavior, Animal/drug effects ; Brain/drug effects ; Brain/enzymology ; Brain/physiopathology ; Chronic Pain/drug therapy ; Chronic Pain/enzymology ; Chronic Pain/physiopathology ; Disease Models, Animal ; Enzyme Inhibitors/pharmacokinetics ; Enzyme Inhibitors/pharmacology ; Ethanolamines/metabolism ; Male ; Neuralgia/drug therapy ; Neuralgia/enzymology ; Neuralgia/physiopathology ; Oleic Acids/metabolism ; Pain Threshold/drug effects ; Palmitic Acids/metabolism ; Piperidines/pharmacokinetics ; Piperidines/pharmacology ; Pyridines/pharmacokinetics ; Pyridines/pharmacology ; Rats, Sprague-Dawley
Chemical Substances	ASP8477 ; Amides ; Analgesics ; Enzyme Inhibitors ; Ethanolamines ; Oleic Acids ; Oleylethanolamide ; Palmitic Acids ; Piperidines ; Pyridines ; palmidrol (6R8T1UDM3V) ; Amidohydrolases (EC 3.5.-) ; fatty-acid amide hydrolase (EC 3.5.1.-)
Language	English
Publishing date	2020-05-21
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2020.173194
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Article ; Online: In vitro and in vivo pharmacological characterization of ASP8477: A novel highly selective fatty acid amide hydrolase inhibitor.

Watabiki, Tomonari / Tsuji, Noriko / Kiso, Tetsuo / Ozawa, Tohru / Narazaki, Fumie / Kakimoto, Shuichiro

European journal of pharmacology

2017 Volume 815, Page(s) 42–48

Abstract: Although exogenous agonists for cannabinoid (CB) receptors are clinically effective for treating chronic pain, global activation of brain CB receptors causes frequent central nervous system (CNS) side-effects. Fatty acid amide hydrolase (FAAH) is a ... ...

Abstract	Although exogenous agonists for cannabinoid (CB) receptors are clinically effective for treating chronic pain, global activation of brain CB receptors causes frequent central nervous system (CNS) side-effects. Fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme for anandamide (AEA), an endogenous CB. Recently, we discovered a novel FAAH inhibitor, 3-pyridyl 4-(phenylcarbamoyl)piperidine-1-carboxylate (ASP8477). In vitro studies demonstrated that ASP8477 inhibited human FAAH-1, FAAH-1 (P129T) and FAAH-2 activity with IC
Language	English
Publishing date	2017-11-15
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2017.10.007
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Article ; Online: Analgesic effects of novel lysophosphatidic acid receptor 5 antagonist AS2717638 in rodents.

Murai, Nobuhito / Hiyama, Hideki / Kiso, Tetsuo / Sekizawa, Toshihiro / Watabiki, Tomonari / Oka, Hiromasa / Aoki, Toshiaki

Neuropharmacology

2017 Volume 126, Page(s) 97–107

Abstract: Lysophosphatidic acid (LPA) is a bioactive lipid that acts via at least six G protein-coupled receptors, LPA receptors 1-6 (LPA1-6), for various physiological functions. We examined (1) whether LPA5 is involved in pain signaling in the spinal cord; and ( ... ...

Abstract	Lysophosphatidic acid (LPA) is a bioactive lipid that acts via at least six G protein-coupled receptors, LPA receptors 1-6 (LPA1-6), for various physiological functions. We examined (1) whether LPA5 is involved in pain signaling in the spinal cord; and (2) the pharmacological effects of a novel LPA5 antagonist on intrathecal prostaglandin (PG)- and (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced allodynia, and neuropathic and inflammatory pain in rodents. Intrathecal injection of a selective LPA5 agonist, geranylgeranyl diphosphate, and a non-selective agonist, LPA, induced allodynia in wild type, but not in LPA5 knockout mice. These novel results suggest that LPA5 is important for pain signal transmission in the spinal cord. AS2717638 (6,7-dimethoxy-2-(5-methyl-1,2-benzoxazol-3-yl)-4-(piperidin-1-ylcarbonyl)isoquinolin-1(2H)-one) bound to the LPA-binding site on LPA5 and selectively inhibited LPA-induced cyclic adenosine monophosphate accumulation in human LPA5-but not LPA1-, 2-, or 3-expressing cells. Further, oral administration of AS2717638 inhibited LPA5 agonist-induced allodynia in mice. AS2717638 also significantly improved PGE
MeSH term(s)	Analgesics/pharmacology ; Animals ; Benzoxazoles/pharmacology ; Cells, Cultured ; Cyclic AMP/metabolism ; Female ; Hyperalgesia/chemically induced ; Hyperalgesia/prevention & control ; Inflammation/complications ; Injections, Spinal ; Isoquinolines/pharmacology ; Lysophospholipids/administration & dosage ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Neuralgia ; Pain/metabolism ; Pain/prevention & control ; Pain Threshold/drug effects ; Piperidines/pharmacology ; Polyisoprenyl Phosphates/administration & dosage ; Rats, Inbred Lew ; Rats, Sprague-Dawley ; Receptors, Lysophosphatidic Acid/antagonists & inhibitors ; Receptors, Lysophosphatidic Acid/genetics
Chemical Substances	AS2717638 ; Analgesics ; Benzoxazoles ; Isoquinolines ; LPAR5 protein, mouse ; Lpa5 protein, rat ; Lysophospholipids ; Piperidines ; Polyisoprenyl Phosphates ; Receptors, Lysophosphatidic Acid ; Cyclic AMP (E0399OZS9N) ; geranylgeranyl pyrophosphate (N21T0D88LX) ; lysophosphatidic acid (PG6M3969SG)
Language	English
Publishing date	2017-11
Publishing country	England
Document type	Journal Article
ZDB-ID	218272-5
ISSN	1873-7064 ; 0028-3908
ISSN (online)	1873-7064
ISSN	0028-3908
DOI	10.1016/j.neuropharm.2017.08.032
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Article ; Online: Spontaneous and evoked pain-associated behaviors in a rat model of neuropathic pain respond differently to drugs with different mechanisms of action.

Murai, Nobuhito / Sekizawa, Toshihiro / Gotoh, Takayasu / Watabiki, Tomonari / Takahashi, Masayasu / Kakimoto, Shuichiro / Takahashi, Yuko / Iino, Masanobu / Nagakura, Yukinori

Pharmacology, biochemistry, and behavior

2016 Volume 141, Page(s) 10–17

Abstract: Given that patients with neuropathic pain suffer a mixture of spontaneous and evoked pain symptoms, we assessed the effects of drugs with different mechanism of action on spontaneous and evoked pain-associated behaviors in a rat model of neuropathic pain ...

Abstract	Given that patients with neuropathic pain suffer a mixture of spontaneous and evoked pain symptoms, we assessed the effects of drugs with different mechanism of action on spontaneous and evoked pain-associated behaviors in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. Frequent aberrant limb movement on the operated side was measured to assess spontaneous pain-associated behavior, and mechanical allodynia and thermal hyperalgesia were evaluated to assess evoked pain-associated behaviors. These three types of behavior were assessed after administration of the following drugs: pregabalin (α2δ-subunit ligand), morphine (μ-opioid receptor agonist), perampanel (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA] receptor antagonist), clonidine, dexmedetomidine (α2-adrenoceptor agonists), and diclofenac (non-steroidal anti-inflammatory drug [NSAID]). Pregabalin at an oral dose of 10 or 30mg/kg significantly alleviated frequent aberrant limb movement and mechanical allodynia, but not thermal hyperalgesia. Morphine at a subcutaneous dose of 1 or 3mg/kg significantly improved all three types of behavior. Perampanel at an oral dose of 1mg/kg attenuated only frequent aberrant limb movement. Intraperitoneal administration of clonidine (0.01 or 0.03mg/kg) and dexmedetomidine (0.03mg/kg) significantly improved all three types of behavior, while diclofenac did not relieve any of the behaviors. Pregabalin, clonidine, and dexmedetomidine significantly decreased motor performance at doses close to analgesic doses in the rotarod test. The present study demonstrates that responses to spontaneous and evoked pain symptoms in neuropathic pain condition differ depending on a drug's mechanism of action. The selection and application of drugs according to the specific symptoms would be considered for the medication of patients with neuropathic pain.
MeSH term(s)	Analgesics/therapeutic use ; Animals ; Disease Models, Animal ; Male ; Neuralgia/drug therapy ; Neuralgia/physiopathology ; Rats ; Rats, Sprague-Dawley
Chemical Substances	Analgesics
Language	English
Publishing date	2016-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	191042-5
ISSN	1873-5177 ; 0091-3057
ISSN (online)	1873-5177
ISSN	0091-3057
DOI	10.1016/j.pbb.2015.11.008
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Article ; Online: Intrathecal administration of AS1928370, a transient receptor potential vanilloid 1 antagonist, attenuates mechanical allodynia in a mouse model of neuropathic pain.

Watabiki, Tomonari / Kiso, Tetsuo / Tsukamoto, Mina / Aoki, Toshiaki / Matsuoka, Nobuya

Biological & pharmaceutical bulletin

2011 Volume 34, Issue 7, Page(s) 1105–1108

Abstract: Transient receptor potential vanilloid 1 (TRPV1) is primarily expressed in central and peripheral terminals of non-myelinated primary afferent neurons. We previously showed that AS1928370, a novel TRPV1 antagonist that can prevent ligand-induced ... ...

Abstract	Transient receptor potential vanilloid 1 (TRPV1) is primarily expressed in central and peripheral terminals of non-myelinated primary afferent neurons. We previously showed that AS1928370, a novel TRPV1 antagonist that can prevent ligand-induced activation but not proton-induced activation, ameliorates neuropathic pain in rats without hyperthermic effect. In this study, we investigated its analgesic profile in mice. AS1928370 showed good oral bioavailability and high penetration into the brain and spinal cord in mice. The mean plasma-to-brain and plasma-to-spinal cord ratios were 4.3 and 3.5, respectively. Pretreatment with AS1928370 significantly suppressed both capsaicin-induced acute pain and withdrawal response in hot plate test at 10-30 mg/kg per os (p.o.). At lower oral doses (0.3-1.0 mg/kg), AS1928370 improved mechanical allodynia in mice undergoing spinal nerve ligation. Intrathecal administration of AS1928370 (30 µg/body) also significantly suppressed mechanical allodynia. In addition, AS1928370 showed no effect on locomotor activity up to 30 mg/kg p.o. These results suggest that spinal TRPV1 has an important role in the transmission of neuropathic pain and that the central nervous system (CNS) penetrant TRPV1 receptor antagonist AS1928370 is a promising candidate for treating neuropathic pain.
MeSH term(s)	Animals ; Benzamides/administration & dosage ; Benzamides/pharmacokinetics ; Benzamides/pharmacology ; Capsaicin/pharmacology ; Disease Models, Animal ; Hyperalgesia/prevention & control ; Injections, Spinal ; Mice ; Neuralgia/chemically induced ; Neuralgia/prevention & control ; Quinolones/administration & dosage ; Quinolones/pharmacokinetics ; Quinolones/pharmacology ; TRPV Cation Channels/antagonists & inhibitors ; Tissue Distribution
Chemical Substances	Benzamides ; N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-((2-methylpyrrolidin-1-yl)methyl)biphenyl-4-carboxamide ; Quinolones ; TRPV Cation Channels ; Capsaicin (S07O44R1ZM)
Language	English
Publishing date	2011-06-25
Publishing country	Japan
Document type	Journal Article
ZDB-ID	1150271-x
ISSN	1347-5215 ; 0918-6158
ISSN (online)	1347-5215
ISSN	0918-6158
DOI	10.1248/bpb.34.1105
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Article ; Online: Systemic administration of 5-HT(2C) receptor agonists attenuates muscular hyperalgesia in reserpine-induced myalgia model.

Ogino, Shinichi / Nagakura, Yukinori / Tsukamoto, Mina / Watabiki, Tomonari / Ozawa, Tohru / Oe, Tomoya / Shimizu, Yasuaki / Ito, Hiroyuki

Pharmacology, biochemistry, and behavior

2013 Volume 108, Page(s) 8–15

Abstract: Fibromyalgia is a prevalent musculoskeletal disorder characterized by chronic widespread pain that significantly reduces quality of life in patients. Due to the lack of consistently effective treatment, the development of improved therapies for treating ... ...

Abstract	Fibromyalgia is a prevalent musculoskeletal disorder characterized by chronic widespread pain that significantly reduces quality of life in patients. Due to the lack of consistently effective treatment, the development of improved therapies for treating fibromyalgia is necessary. As dysfunction of serotonergic analgesic control appears to be involved in the pathophysiology of fibromyalgia, the present study explored the potential of 5-HT(2C) receptor agonists as novel therapies for treating this disease. Three 5-HT(2C) receptor agonists (lorcaserin, vabicaserin and YM348) that have been suggested to be useful in the treatment of several central nervous system diseases, including obesity and schizophrenia, were used. The effect of systemic administration of these agents on the muscular hyperalgesia that develops in the reserpine-induced myalgia (RIM) rat, a putative animal model of fibromyalgia, was investigated. RIM rats exhibited decreased muscle pressure thresholds. Microdialysis experiments showed that the concentration of serotonin (5-HT) in the spinal cord of RIM rats was significantly lower than that of controls. Lorcaserin (0.3-3 mg/kg p.o.), vabicaserin (0.3-3 mg/kg s.c.) and YM348 (0.03-0.3 mg/kg p.o.) recovered the muscle pressure threshold. The effect of lorcaserin was reversed by the pretreatment with SB242084, a 5-HT(2C) receptor antagonist. Our findings demonstrate that 5-HT(2C) receptors play a critical role in muscular hyperalgesia in RIM rats and suggest that 5-HT(2C) receptor agonists have therapeutic potential for treating chronic pain in patients with fibromyalgia although clinical extrapolation remains to be a future challenge.
MeSH term(s)	Animals ; Hyperalgesia/chemically induced ; Hyperalgesia/drug therapy ; Locomotion/drug effects ; Microdialysis ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/pathology ; Rats ; Rats, Sprague-Dawley ; Receptor, Serotonin, 5-HT2C/drug effects ; Reserpine/administration & dosage ; Serotonin/analysis ; Serotonin Receptor Agonists/administration & dosage ; Serotonin Receptor Agonists/pharmacology ; Serotonin Receptor Agonists/therapeutic use ; Spinal Cord/chemistry ; Spinal Cord/drug effects
Chemical Substances	Receptor, Serotonin, 5-HT2C ; Serotonin Receptor Agonists ; Serotonin (333DO1RDJY) ; Reserpine (8B1QWR724A)
Language	English
Publishing date	2013-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	191042-5
ISSN	1873-5177 ; 0091-3057
ISSN (online)	1873-5177
ISSN	0091-3057
DOI	10.1016/j.pbb.2013.04.007
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Article ; Online: Amelioration of neuropathic pain by novel transient receptor potential vanilloid 1 antagonist AS1928370 in rats without hyperthermic effect.

Watabiki, Tomonari / Kiso, Tetsuo / Kuramochi, Takahiro / Yonezawa, Koichi / Tsuji, Noriko / Kohara, Atsuyuki / Kakimoto, Shuichiro / Aoki, Toshiaki / Matsuoka, Nobuya

The Journal of pharmacology and experimental therapeutics

2011 Volume 336, Issue 3, Page(s) 743–750

Abstract: Transient receptor potential vanilloid 1 (TRPV1) is activated by a variety of stimulations, such as endogenous ligands and low pH, and is believed to play a role in pain transmission. TRPV1 antagonists have been reported to be effective in several animal ...

Abstract	Transient receptor potential vanilloid 1 (TRPV1) is activated by a variety of stimulations, such as endogenous ligands and low pH, and is believed to play a role in pain transmission. TRPV1 antagonists have been reported to be effective in several animal pain models; however, some compounds induce hyperthermia in animals and humans. We discovered the novel TRPV1 antagonist (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide (AS1928370) in our laboratory. AS1928370 bound to the resiniferatoxin-binding site on TRPV1 and inhibited capsaicin-mediated inward currents with an IC₅₀ value of 32.5 nM. Although AS1928370 inhibited the capsaicin-induced Ca²(+) flux in human and rat TRPV1-expressing cells, the inhibitory effect on proton-induced Ca²(+) flux was extremely small. In addition, AS1928370 showed no inhibitory effects on transient receptor potential vanilloid 4, transient receptor potential ankyrin 1, and transient receptor potential melastatin 8 in concentrations up to 10 μM. AS1928370 improved capsaicin-induced secondary hyperalgesia and mechanical allodynia in an L5/L6 spinal nerve ligation model in rats with respective ED₅₀ values of 0.17 and 0.26 mg/kg p.o. Furthermore, AS1928370 alleviated inflammatory pain in a complete Freund's adjuvant model at 10 mg/kg p.o. AS1928370 had no effect on rectal body temperature up to 10 mg/kg p.o., although a significant hypothermic effect was noted at 30 mg/kg p.o. In addition, AS1928370 showed no significant effect on motor coordination. These results suggest that blockage of the TRPV1 receptor without affecting the proton-mediated TRPV1 activation is a promising approach to treating neuropathic pain because of the potential wide safety margin against hyperthermic effects. As such, compounds such as ASP1928370 may have potential as new analgesic agents for treating neuropathic pain.
MeSH term(s)	Analgesics/pharmacology ; Analgesics/therapeutic use ; Animals ; Benzamides/chemistry ; Benzamides/pharmacology ; Benzamides/therapeutic use ; Capsaicin/pharmacology ; Capsaicin/therapeutic use ; Fever/chemically induced ; HEK293 Cells ; Humans ; Male ; Neuralgia/drug therapy ; Neuralgia/physiopathology ; Pain/drug therapy ; Pain/physiopathology ; Pain Measurement/drug effects ; Pain Measurement/methods ; Protein Binding/physiology ; Quinolones/chemistry ; Quinolones/pharmacology ; Quinolones/therapeutic use ; Rats ; Rats, Sprague-Dawley ; TRPV Cation Channels/antagonists & inhibitors ; TRPV Cation Channels/physiology
Chemical Substances	Analgesics ; Benzamides ; N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-((2-methylpyrrolidin-1-yl)methyl)biphenyl-4-carboxamide ; Quinolones ; TRPV Cation Channels ; Trpv1 protein, rat ; Capsaicin (S07O44R1ZM)
Language	English
Publishing date	2011-03
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.110.175570
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Article ; Online: Assessment of canine sensory function by using sine-wave electrical stimuli paradigm.

Watabiki, Tomonari / Nagakura, Yukinori / Wegner, Kirsten / Kakimoto, Shuichiro / Tozier, Nicolle A / Malkmus, Shelle A / Yaksh, Tony L

Physiology & behavior

2010 Volume 101, Issue 3, Page(s) 327–330

Abstract: The paradigm of sine-wave electrical stimuli has been used for sensory neurological assessment in humans. In the present study, we applied the paradigm to the dog for the quantitative assessment of sensory function. Sine-wave electrical current stimuli ... ...

Abstract	The paradigm of sine-wave electrical stimuli has been used for sensory neurological assessment in humans. In the present study, we applied the paradigm to the dog for the quantitative assessment of sensory function. Sine-wave electrical current stimuli at frequencies of 2000, 250, and 5Hz were delivered to bipolar electrodes attached to the skin surface of the hind paws. The stimulation intensity was gradually increased, and the minimum intensity required to elicit the lifting behavior in the stimulated paw was determined as current threshold (CT) for each of the three frequencies. Dogs consistently showed the lifting behavior at CTs without showing aversive behaviors such as vocalization and wriggling. The baseline CTs (mean+/-SEM, n=12) were 4430+/-110microA for CT2000, 2215+/-173microA for CT250, and 2305+/-152microA for CT5. The CTs immediately increased after bolus intravenous injection of fentanyl at 10microg/kg, although the significant increase disappeared within 1h. The time course for the CTs was parallel to that of plasma fentanyl concentration. In conclusion, the present study applied the paradigm of transcutaneous sine-wave electrical stimuli to the dog, and used the hind paw lifting as endpoint behavior. This paradigm is simple, non-invasive, useful in the assessment of sensory function, and can be adapted to investigate the pharmacokinetics/pharmacodynamics relation of drugs. Further studies are needed to give the conclusive interpretation of the endpoint behavior.
MeSH term(s)	Analgesics, Opioid/pharmacokinetics ; Analgesics, Opioid/pharmacology ; Analysis of Variance ; Animals ; Dogs/physiology ; Dose-Response Relationship, Drug ; Fentanyl/pharmacokinetics ; Fentanyl/pharmacology ; Male ; Models, Animal ; Reference Standards ; Sensory Thresholds/drug effects ; Sensory Thresholds/physiology ; Statistics, Nonparametric ; Transcutaneous Electric Nerve Stimulation/methods
Chemical Substances	Analgesics, Opioid ; Fentanyl (UF599785JZ)
Language	English
Publishing date	2010-10-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	3907-x
ISSN	1873-507X ; 0031-9384
ISSN (online)	1873-507X
ISSN	0031-9384
DOI	10.1016/j.physbeh.2010.05.019
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Article: Minodronic acid, a third-generation bisphosphonate, antagonizes purinergic P2X(2/3) receptor function and exerts an analgesic effect in pain models.

Kakimoto, Shuichiro / Nagakura, Yukinori / Tamura, Seiji / Watabiki, Tomonari / Shibasaki, Kumiko / Tanaka, Shohei / Mori, Masamichi / Sasamata, Masao / Okada, Masamichi

European journal of pharmacology

2008 Volume 589, Issue 1-3, Page(s) 98–101

Abstract: The P2X(2/3) receptor has an important role in the nociceptive transmission. Minodronic acid is a third third-generation bisphosphonate and a potent inhibitor of bone resorption. We found that minodronic acid inhibited alpha,beta-methylene ATP-induced ... ...

Abstract	The P2X(2/3) receptor has an important role in the nociceptive transmission. Minodronic acid is a third third-generation bisphosphonate and a potent inhibitor of bone resorption. We found that minodronic acid inhibited alpha,beta-methylene ATP-induced cation uptake with the potency higher than that of suramin in the P2X(2/3) receptor receptor-expressing cells. Other bisphosphonates did not show such activity. Subcutaneously administered (10-50 mg/kg) minodronic acid significantly inhibited the alpha,beta-methylene ATP-, acetic acid- and formalin-induced nociceptive behaviors in mice. These unique effects of minodronic acid would be beneficial for the treatment of accelerated bone turnover diseases accompanied by bone pain, including bone metastases.
MeSH term(s)	Acetic Acid ; Adenosine Triphosphate/analogs & derivatives ; Analgesics, Non-Narcotic/administration & dosage ; Analgesics, Non-Narcotic/pharmacology ; Animals ; Bone Density Conservation Agents/administration & dosage ; Bone Density Conservation Agents/pharmacology ; CHO Cells ; Cricetinae ; Cricetulus ; Diphosphonates/administration & dosage ; Diphosphonates/pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Formaldehyde ; Imidazoles/administration & dosage ; Imidazoles/pharmacology ; Injections, Subcutaneous ; Male ; Mice ; Mice, Inbred ICR ; Pain/chemically induced ; Pain/metabolism ; Pain/prevention & control ; Pain Measurement ; Purinergic P2 Receptor Antagonists ; Receptors, Purinergic P2/genetics ; Receptors, Purinergic P2/metabolism ; Receptors, Purinergic P2X2 ; Receptors, Purinergic P2X3 ; Time Factors ; Transfection
Chemical Substances	Analgesics, Non-Narcotic ; Bone Density Conservation Agents ; Diphosphonates ; Imidazoles ; P2rx2 protein, mouse ; P2rx3 protein, mouse ; Purinergic P2 Receptor Antagonists ; Receptors, Purinergic P2 ; Receptors, Purinergic P2X2 ; Receptors, Purinergic P2X3 ; YM 529 (127657-42-5) ; Formaldehyde (1HG84L3525) ; Adenosine Triphosphate (8L70Q75FXE) ; alpha,beta-methyleneadenosine 5'-triphosphate (NYX13NT29D) ; Acetic Acid (Q40Q9N063P)
Language	English
Publishing date	2008-07-28
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2008.05.011
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Antinociceptive profile of a selective metabotropic glutamate receptor 1 antagonist YM-230888 in chronic pain rodent models.

Kohara, Atsuyuki / Nagakura, Yukinori / Kiso, Tetsuo / Toya, Takashi / Watabiki, Tomonari / Tamura, Seiji / Shitaka, Yoshitsugu / Itahana, Hirotsune / Okada, Masamichi

European journal of pharmacology

2007 Volume 571, Issue 1, Page(s) 8–16

Abstract: Metabotropic glutamate receptor 1 (mGlu(1) receptor) has been suggested to play an important role in pain transmission. In this study, the effects of a newly-synthesized mGlu(1) receptor antagonist, (R)-N-cycloheptyl-6-({[(tetrahydro-2-furyl)methyl]amino} ...

Abstract	Metabotropic glutamate receptor 1 (mGlu(1) receptor) has been suggested to play an important role in pain transmission. In this study, the effects of a newly-synthesized mGlu(1) receptor antagonist, (R)-N-cycloheptyl-6-({[(tetrahydro-2-furyl)methyl]amino}methyl)thieno[2,3-d]pyrimidin-4-ylamine (YM-230888), were examined in a variety of rodent chronic pain models in order to characterize the potential analgesic profile of mGlu(1) receptor blockade. YM-230888 bound an allosteric site of mGlu(1) receptor with a K(i) value of 13+/-2.5 nM and inhibited mGlu(1)-mediated inositol phosphate production in rat cerebellar granule cells with an IC(50) value of 13+/-2.4 nM. It showed selectivity for mGlu(1) versus mGlu(2)-mGlu(7) subtypes and ionotropic glutamate receptors. YM-230888 recovered mechanical allodynia with an ED(50) value of 8.4 mg/kg p.o. in L5/L6 spinal nerve ligation models. It also showed antinociceptive response at doses of 10 and 30 mg/kg p.o. in streptozotocin-induced hyperalgesia models. In addition, it significantly reduced pain parameters at a dose of 30 mg/kg p.o. in complete Freund's adjuvant-induced arthritic pain models. Although YM-230888 showed no significant effect on rotarod performance time at doses of 10 or 30 mg/kg p.o., it significantly decreased it at a dose of 100 mg/kg p.o. On the other hand, YM-230888 showed no significant sedative effect in locomotor activity measurement up to 100 mg/kg p.o. These results suggest that the blockade of mGlu(1) receptors is an attractive target for analgesics. YM-230888 has potential as a new analgesic agent for the treatment of various chronic pain conditions. In addition, YM-230888 may be a useful tool for the investigation of mGlu(1) receptors.
MeSH term(s)	Analgesics/metabolism ; Analgesics/pharmacokinetics ; Analgesics/pharmacology ; Animals ; Arthritis, Experimental/physiopathology ; Arthritis, Experimental/prevention & control ; Benzimidazoles/metabolism ; Binding, Competitive ; Cell Line ; Cells, Cultured ; Chronic Disease ; Cycloheptanes/metabolism ; Cycloheptanes/pharmacokinetics ; Cycloheptanes/pharmacology ; Dose-Response Relationship, Drug ; Humans ; Kinetics ; Ligation/adverse effects ; Molecular Structure ; Motor Activity/drug effects ; Pain/etiology ; Pain/physiopathology ; Pain/prevention & control ; Pain Measurement/drug effects ; Pain Measurement/methods ; Pyrimidines/metabolism ; Pyrimidines/pharmacokinetics ; Pyrimidines/pharmacology ; Radioligand Assay ; Rats ; Rats, Inbred Lew ; Rats, Sprague-Dawley ; Rats, Wistar ; Receptors, Metabotropic Glutamate/antagonists & inhibitors ; Receptors, Metabotropic Glutamate/metabolism ; Spinal Nerves/surgery ; Thiazoles/metabolism ; Tritium
Chemical Substances	(R)-N-cycloheptyl-6-((((tetrahydro-2-furyl)methyl)amino)methyl)thieno(2,3-d)pyrimidin-4-ylamine ; 6-amino-N-cyclohexyl-N,3-dimethylthiazolo(3,2-a)benzimidazole-2-carboxamide ; Analgesics ; Benzimidazoles ; Cycloheptanes ; Pyrimidines ; Receptors, Metabotropic Glutamate ; Thiazoles ; metabotropic glutamate receptor type 1 ; Tritium (10028-17-8)
Language	English
Publishing date	2007-09-24
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2007.05.030
Database	MEDical Literature Analysis and Retrieval System OnLINE

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