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Article: A K

Takeshita, Nobuaki / Oe, Tomoya / Kiso, Tetsuo / Kakimoto, Shuichiro

2021 Volume 14, Page(s) 23–34

Abstract: Purpose: Although abnormal peripheral and central pain processing has been observed in fibromyalgia (FM) patients, the biomechanics and pathophysiology, surrounding the peripheral mechanism are not well understood. An intermediate conductance channel, K! ...

Abstract	Purpose: Although abnormal peripheral and central pain processing has been observed in fibromyalgia (FM) patients, the biomechanics and pathophysiology, surrounding the peripheral mechanism are not well understood. An intermediate conductance channel, K Methods: Human or rat K Results: ASP0819 increased the negative membrane potential in a concentration-dependent manner. Oral administration of ASP0819 significantly recovered the decrease in muscle pressure threshold in rat FM models of RIM and VIM. The in vivo electrophysiological experiments showed that Aδ- and C-fibers innervating the leg muscles in the RIM model demonstrated increased spontaneous and mechanically evoked firing compared with normal rats. Intravenous infusion of ASP0819 significantly reduced both the spontaneous activity and mechanically evoked responses in Aδ-fibers in the rat RIM model. ASP0819 significantly reduced the number of abdominal contractions as an indicator of abdominal pain behaviors in the rat visceral extension model and withdrawal responses in the osteoarthritis model, respectively. Conclusion: These findings suggest that ASP0819 may be a promising analgesic agent with the ability to modulate peripheral pain signal transmission. Its use in the treatment of several pain conditions should be explored, chief amongst these being FM pain.
Language	English
Publishing date	2021-01-12
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2495284-9
ISSN	1178-7090
ISSN	1178-7090
DOI	10.2147/JPR.S274563
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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

European journal of pharmacology

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: Effects of pregabalin and duloxetine on neurotransmitters in the dorsal horn of the spinal cord in a rat model of fibromyalgia.

Kiso, Tetsuo / Moriyama, Ai / Furutani, Masako / Matsuda, Ritsuko / Funatsu, Yukiko

European journal of pharmacology

2018 Volume 827, Page(s) 117–124

Abstract: Dysfunction of the monoamine systems in the nervous system is associated with the clinical symptoms of fibromyalgia. Reserpine-induced myalgia (RIM) rats are a putative model of fibromyalgia in which muscle pressure thresholds and monoamine content is ... ...

Abstract	Dysfunction of the monoamine systems in the nervous system is associated with the clinical symptoms of fibromyalgia. Reserpine-induced myalgia (RIM) rats are a putative model of fibromyalgia in which muscle pressure thresholds and monoamine content is reduced in the brain and spinal cord. We examined the effects of pregabalin and duloxetine, drugs approved for fibromyalgia treatment, on the levels of extracellular neurotransmitters in the dorsal horn of the spinal cord in RIM rats using microdialysis. Male SD rats were used for all experiments. To generate RIM rats, reserpine was injected at 1 mg/kg subcutaneously once daily for three consecutive days. The pressure threshold of the mid-gastrocnemius muscle was measured using a Randall-Selitto apparatus. Norepinephrine, dopamine, and serotonin were detected using high-performance liquid chromatography with electrochemical detection, and glutamate and γ-aminobutyric acid (GABA) were detected using liquid chromatography-mass spectrometry. The muscle pressure threshold in RIM rats was significantly lower than that in normal rats. While the levels of monoamines and glutamate were lower in the spinal cord of RIM rats than in normal rats, levels of GABA did not markedly differ. Duloxetine increased the levels of all three monoamines in normal and RIM rats in a dose-dependent manner. In contrast, pregabalin only increased norepinephrine levels in RIM rats. These results indicate that while both pregabalin and duloxetine ameliorate muscle pressure thresholds in RIM rats, their effects on the levels of extracellular neurotransmitters in the spinal cord differ considerably.
MeSH term(s)	Animals ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Duloxetine Hydrochloride/pharmacology ; Fibromyalgia/metabolism ; Fibromyalgia/pathology ; Male ; Neurotransmitter Agents/metabolism ; Pregabalin/pharmacology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord Dorsal Horn/drug effects ; Spinal Cord Dorsal Horn/metabolism
Chemical Substances	Neurotransmitter Agents ; Pregabalin (55JG375S6M) ; Duloxetine Hydrochloride (9044SC542W)
Language	English
Publishing date	2018-03-09
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.2018.03.011
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Article ; Online: Analgesic effects of ASP3662, a novel 11β-hydroxysteroid dehydrogenase 1 inhibitor, in rat models of neuropathic and dysfunctional pain.

Kiso, Tetsuo / Sekizawa, Toshihiro / Uchino, Hiroshi / Tsukamoto, Mina / Kakimoto, Shuichiro

British journal of pharmacology

2018 Volume 175, Issue 19, Page(s) 3784–3796

Abstract: Background and purpose: Glucocorticoids are a major class of stress hormones known to participate in stress-induced hyperalgesia. Although 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) is a key enzyme in the intracellular regeneration of glucocorticoids ...

Abstract	Background and purpose: Glucocorticoids are a major class of stress hormones known to participate in stress-induced hyperalgesia. Although 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) is a key enzyme in the intracellular regeneration of glucocorticoids in the CNS, its role in pain perception has not been assessed. Here, we examined the effects of ASP3662, a novel 11β-HSD1 inhibitor, on neuropathic and dysfunctional pain. Experimental approach: The enzyme inhibitory activities and pharmacokinetics of ASP3662 were examined, and its antinociceptive effects were evaluated in models of neuropathic pain, fibromyalgia and inflammatory pain in Sprague-Dawley rats. Key results: ASP3662 inhibited human, mouse and rat 11β-HSD1 but not human 11β-HSD2, in vitro. ASP3662 had no significant effect on 87 other possible targets (enzymes, transporters and receptors). ASP3662 inhibited in vitro conversion of glucocorticoid from its inactive to active form in extracts of rat brain and spinal cord. Pharmacokinetic analysis in Sprague-Dawley rats showed that ASP3662 has CNS-penetrability and long-lasting pharmacokinetic properties. Single oral administration of ASP3662 ameliorated mechanical allodynia in spinal nerve ligation (SNL) and streptozotocin-induced diabetic rats and thermal hyperalgesia in chronic constriction nerve injury rats. ASP3662 also restored muscle pressure thresholds in reserpine-induced myalgia rats. Intrathecal administration of ASP3662 was also effective in SNL rats. However, ASP3662 had no analgesic effects in adjuvant-induced arthritis rats. Conclusions and implications: ASP3662 is a potent, selective and CNS-penetrable inhibitor of 11β-HSD1. The effects of ASP3662 suggest that selective inhibition of 11β-HSD1 may be an attractive approach for the treatment of neuropathic and dysfunctional pain, as observed in fibromyalgia.
MeSH term(s)	11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors ; 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism ; Administration, Oral ; Analgesics/administration & dosage ; Analgesics/chemistry ; Analgesics/pharmacology ; Animals ; Benzamides/administration & dosage ; Benzamides/chemistry ; Benzamides/pharmacology ; Diabetes Mellitus, Experimental/chemically induced ; Diabetes Mellitus, Experimental/drug therapy ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/administration & dosage ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Male ; Pain/chemically induced ; Pain/drug therapy ; Rats ; Rats, Sprague-Dawley ; Streptozocin/antagonists & inhibitors ; Structure-Activity Relationship ; Triazoles/administration & dosage ; Triazoles/chemistry ; Triazoles/pharmacology
Chemical Substances	ASP3662 ; Analgesics ; Benzamides ; Enzyme Inhibitors ; Triazoles ; Streptozocin (5W494URQ81) ; 11-beta-Hydroxysteroid Dehydrogenase Type 1 (EC 1.1.1.146)
Language	English
Publishing date	2018-08-17
Publishing country	England
Document type	Journal Article
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.14448
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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: 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: 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: Spinal mechanism of standard analgesics: evaluation using mouse models of allodynia.

Tsukamoto, Mina / Kiso, Tetsuo / Shimoshige, Yukinori / Aoki, Toshiaki / Matsuoka, Nobuya

European journal of pharmacology

2010 Volume 634, Issue 1-3, Page(s) 40–45

Abstract: Spinal neurotransmission plays an important role in the perception of pain signaling. In the present study, we investigated the spinal anti-nociceptive mechanism of current standard analgesics in mouse models of tactile allodynia induced by intrathecal ... ...

Abstract	Spinal neurotransmission plays an important role in the perception of pain signaling. In the present study, we investigated the spinal anti-nociceptive mechanism of current standard analgesics in mouse models of tactile allodynia induced by intrathecal administration of N-methyl-D-aspartic acid (NMDA), prostaglandin E2 (PGE2), and bicuculline. NMDA-induced allodynia is induced by postsynaptic NMDA receptor activation, while PGE2-induced allodynia is triggered by the enhancement of presynaptic glutamate release via EP1 receptor activation. In contrast, bicuculline induces allodynia by the blockade of gamma-aminobutyric acid (GABA)A receptor-mediated inhibitory system. As the clinically available analgesics, pregabalin (alpha2delta-subunit calcium channel ligand), ziconotide (N-type calcium channel blocker), mexiletine (sodium channel blocker), and duloxetine (serotonin and norepinephrine reuptake inhibitors) were evaluated in these neurochemically-induced allodynia models. Pregabalin almost completely alleviated NMDA-, PGE2-, and bicuculline-induced allodynia. Despite being classified as an agent with a similar molecular target mechanism, ziconotide could only alleviate PGE2-induced allodynia, but not NMDA- or bicuculline-induced allodynia, as did mexiletine and duloxetine. These results taken together suggest that ziconotide, mexiletine, and duloxetine suppress spinal hyperactivity via the presynaptic site mechanism. In contrast, pregabalin could suppress via the downstream step during spinal hyperactivation such as postsynaptic NMDA activation or dysfunction of GABAergic control in addition to presynaptic mechanism. In conclusion, present findings provide implication that the spinal anti-nociceptive mechanistic site of pregabalin is different from that of ziconotide, mexiletine, and duloxetine, and pregabalin could have a broader anti-nociceptive mechanism other than N-type calcium channel blockade.
MeSH term(s)	Analgesics/administration & dosage ; Analgesics/standards ; Animals ; Disease Models, Animal ; Injections, Spinal ; Male ; Mice ; Mice, Inbred ICR ; Pain/drug therapy ; Pain/metabolism ; Pain Measurement/drug effects ; Pain Measurement/methods ; Pain Measurement/standards ; Spinal Cord/drug effects ; Spinal Cord/metabolism
Chemical Substances	Analgesics
Language	English
Publishing date	2010-05-25
Publishing country	Netherlands
Document type	Comparative Study ; Evaluation Studies ; Journal Article
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2010.02.025
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Article: Enhanced insulin secretion and sensitization in diabetic mice on chronic treatment with a transient receptor potential vanilloid 1 antagonist

Tanaka, Hirotsugu / Shimaya, Akiyoshi / Kiso, Tetsuo / Kuramochi, Takahiro / Shimokawa, Teruhiko / Shibasaki, Masayuki

Life sciences. 2011 Mar. 14, v. 88, no. 11-12

2011

Abstract: AIMS: Inhibition of transient receptor potential vanilloid 1 (TRPV1) suppresses calcitonin gene-related peptide (CGRP) secretion in pancreatic nerve fiber cells, thereby stimulating insulin secretion. We examined the effects of repeat administration of ... ...

Abstract	AIMS: Inhibition of transient receptor potential vanilloid 1 (TRPV1) suppresses calcitonin gene-related peptide (CGRP) secretion in pancreatic nerve fiber cells, thereby stimulating insulin secretion. We examined the effects of repeat administration of the TRPV1 antagonist N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamidte monohydrochloride (BCTC) to ob/ob mice, a model of type 2 diabetes with insulin resistance, on whole body glucose and lipid metabolism. MAIN METHODS: We measured blood parameters, including levels of glucose, insulin, and triglycerides, and performed the oral glucose tolerance test (OGTT) after repeat administration of BCTC to ob/ob mice twice a day for four weeks. KEY FINDINGS: We found that BCTC treatment reduced fasting glucose, triglyceride, and insulin levels in the whole body. The effects were comparable to that of pioglitazone, a major insulin-sensitizing agent. Further, we found that administration of BCTC significantly increased plasma insulin secretion in the OGTT, which differed from the effect of pioglitazone treatment. SIGNIFICANCE: Our study is the first to show the anti-diabetic pharmacological effects of the TRPV1 signal inhibitor BCTC. These findings suggest that TRPV1 antagonists may represent a new class of drugs effective in treating type 2 diabetes mellitus because of their dual effects as insulin sensitizers and secretagogues.
Keywords	antagonists ; blood composition ; calcitonin ; drugs ; fasting ; fiber cells ; glucose ; glucose tolerance tests ; insulin ; insulin resistance ; insulin secretion ; lipid metabolism ; mice ; models ; nerve tissue ; noninsulin-dependent diabetes mellitus ; triacylglycerols
Language	English
Dates of publication	2011-0314
Size	p. 559-563.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2011.01.016
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Article ; Online: Design, synthesis, and biological evaluation of novel biphenyl-4-carboxamide derivatives as orally available TRPV1 antagonists.

Oka, Hiromasa / Yonezawa, Koichi / Kamikawa, Akio / Ikegai, Kazuhiro / Asai, Norio / Shirakami, Shohei / Miyamoto, Satoshi / Watanabe, Toshihiro / Kiso, Tetsuo / Takemoto, Yukihiro / Tamura, Seiji / Kuramochi, Takahiro

Bioorganic & medicinal chemistry

2018 Volume 26, Issue 12, Page(s) 3716–3726

Abstract: A new series of transient receptor potential vanilloid type 1 (TRPV1) antagonists were designed and synthesized from N-(3-hydroxyphenyl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide hydrochloride (8). SAR studies identified (R)-N-(1-methyl-2-oxo-1,2,3, ... ...

Abstract	A new series of transient receptor potential vanilloid type 1 (TRPV1) antagonists were designed and synthesized from N-(3-hydroxyphenyl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide hydrochloride (8). SAR studies identified (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide hydrochloride (ASP8370, 7), as a compound with high aqueous solubility, satisfactory stability in human liver microsomes, and reduced CYP3A4 inhibition. ASP8370 was selected as a clinical development candidate with significant ameliorative effects on neuropathic pain. SAR studies also revealed the structural mechanisms underlying the switching between TRPV1 antagonism and agonism.
MeSH term(s)	Administration, Oral ; Amides/chemistry ; Amides/metabolism ; Amides/therapeutic use ; Anticonvulsants/chemical synthesis ; Anticonvulsants/metabolism ; Anticonvulsants/therapeutic use ; Biphenyl Compounds/chemistry ; Cytochrome P-450 CYP3A/chemistry ; Cytochrome P-450 CYP3A/metabolism ; Drug Design ; HEK293 Cells ; Humans ; Inhibitory Concentration 50 ; Microsomes, Liver/metabolism ; Neuralgia/drug therapy ; Solubility ; Structure-Activity Relationship ; TRPV Cation Channels/antagonists & inhibitors ; TRPV Cation Channels/metabolism
Chemical Substances	Amides ; Anticonvulsants ; Biphenyl Compounds ; TRPV Cation Channels ; TRPV1 protein, human ; diphenyl (2L9GJK6MGN) ; Cytochrome P-450 CYP3A (EC 1.14.14.1)
Language	English
Publishing date	2018-06-02
Publishing country	England
Document type	Journal Article
ZDB-ID	1161284-8
ISSN	1464-3391 ; 0968-0896
ISSN (online)	1464-3391
ISSN	0968-0896
DOI	10.1016/j.bmc.2018.06.001
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