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Article: Asymmetric transfer hydrogenation of unsaturated ketones; factors influencing 1,4- vs 1,2- regio- and enantioselectivity, and alkene vs alkyne directing effects

Hall, Thomas H / Adams, Hannah / Vyas, Vijyesh K / Michael Chu, K.L / Wills, Martin

Tetrahedron. 2021 Jan. 01, v. 77

2021

Abstract: A detailed study has been completed on the asymmetric transfer hydrogenation (ATH) of a series of enones using Ru(II) catalysts. Electron-rich rings adjacent to the CO group reduce the level of CO reduction compared to CC. The ATH reaction can readily ... ...

Abstract	A detailed study has been completed on the asymmetric transfer hydrogenation (ATH) of a series of enones using Ru(II) catalysts. Electron-rich rings adjacent to the CO group reduce the level of CO reduction compared to CC. The ATH reaction can readily discriminate between double and triple bonds adjacent to ketones, reducing the double bond but leaving a triple bond intact in the major product.
Keywords	alkynes ; catalysts ; enantioselectivity ; hydrogenation ; ketones
Language	English
Dates of publication	2021-0101
Publishing place	Elsevier Ltd
Document type	Article
Note	NAL-light
ZDB-ID	204285-x
ISSN	1464-5416 ; 0040-4020 ; 0563-2064
ISSN (online)	1464-5416
ISSN	0040-4020 ; 0563-2064
DOI	10.1016/j.tet.2020.131771
Database	NAL-Catalogue (AGRICOLA)

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Article: Sonographic evaluation of the immediate effects of eccentric heel drop exercise on Achilles tendon and gastrocnemius muscle stiffness using shear wave elastography.

Leung, Wilson K C / Chu, K L / Lai, Christopher

PeerJ

2017 Volume 5, Page(s) e3592

Abstract: Background: Mechanical loading is crucial for muscle and tendon tissue remodeling. Eccentric heel drop exercise has been proven to be effective in the management of Achilles tendinopathy, yet its induced change in the mechanical property (i.e., ... ...

Abstract	Background: Mechanical loading is crucial for muscle and tendon tissue remodeling. Eccentric heel drop exercise has been proven to be effective in the management of Achilles tendinopathy, yet its induced change in the mechanical property (i.e., stiffness) of the Achilles tendon (AT), medial and lateral gastrocnemius muscles (MG and LG) was unknown. Given that shear wave elastography has emerged as a powerful tool in assessing soft tissue stiffness with promising intra- and inter-operator reliability, the objective of this study was hence to characterize the stiffness of the AT, MG and LG in response to an acute bout of eccentric heel drop exercise. Methods: Forty-five healthy young adults (36 males and nine females) performed 10 sets of 15-repetition heel drop exercise on their dominant leg with fully-extended knee, during which the AT and gastrocnemius muscles, but not soleus, were highly stretched. Before and immediately after the heel drop exercise, elastic moduli of the AT, MG and LG were measured by shear wave elastography. Results: After the heel drop exercise, the stiffness of AT increased significantly by 41.8 + 33.5% ( Discussion: The gastrocnemius muscles were shown to bear larger mechanical loads than the AT during an acute bout of eccentric heel drop exercise. The findings from this pilot study shed some light on how and to what extent the AT and gastrocnemius muscles mechanically responds to an isolated set of heel drop exercise. Taken together, appropriate eccentric load might potentially benefit mechanical adaptations of the AT and gastrocnemius muscles in the rehabilitation of patients with Achilles tendinopathy.
Language	English
Publishing date	2017-07-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2703241-3
ISSN	2167-8359
ISSN	2167-8359
DOI	10.7717/peerj.3592
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Article: A CB(2) receptor agonist, A-836339, modulates wide dynamic range neuronal activity in neuropathic rats: contributions of spinal and peripheral CB(2) receptors.

McGaraughty, S / Chu, K L / Dart, M J / Yao, B B / Meyer, M D

Neuroscience

2009 Volume 158, Issue 4, Page(s) 1652–1661

Abstract: We investigated the systemic and site-specific actions of a selective CB(2) receptor agonist, A-836339 on mechanically evoked (10 g von Frey hair) and spontaneous firing of spinal wide dynamic range (WDR) neurons in neuropathic (L5 and L6 ligations) and ... ...

Abstract	We investigated the systemic and site-specific actions of a selective CB(2) receptor agonist, A-836339 on mechanically evoked (10 g von Frey hair) and spontaneous firing of spinal wide dynamic range (WDR) neurons in neuropathic (L5 and L6 ligations) and sham rats. Systemic administration of A-836339 (0.3-3 micromol/kg, i.v.) reduced both evoked and spontaneous WDR neuronal activity in neuropathic, but not sham rats. The effects in neuropathic rats were blocked by pre-administration of a CB(2), but not a CB(1), receptor antagonist. Similar to systemic delivery, intra-spinal injection of A-836339 (0.3 and 1 nmol) also attenuated both von Frey-evoked and spontaneous firing of WDR neurons in neuropathic rats. Intra-spinal injections of A-836339 were ineffective in sham rats. Application of A-836339 (3-30 nmol) onto the ipsilateral L5 dorsal root ganglion (DRG) of neuropathic rats reduced the von Frey-evoked activity of WDR neurons, but spontaneous firing was unaltered. All effects of A-836339 on WDR neuronal activity following either intra-spinal or intra-DRG administration were blocked by pre-administration of a CB(2) receptor antagonist. Pre-administration of a CB(1) receptor antagonist did not alter the site-specific effects of A-836339. Injection of A-836339 (300 nmol) into the neuronal receptive field on the ipsilateral hind paw did not affect evoked or spontaneous firing of WDR neurons. Thus, the current data demonstrate that modulation of spinal neuronal activity by a CB(2) receptor agonist is enhanced following peripheral nerve injury, and further delineate the contribution of spinal and peripheral CB(2) receptors to this modulation.
MeSH term(s)	Action Potentials/drug effects ; Animals ; Bornanes/pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Administration Routes ; Ganglia, Spinal/pathology ; Male ; Neurons/drug effects ; Peripheral Nervous System Diseases/pathology ; Physical Stimulation/methods ; Piperidines/pharmacology ; Pyrazoles/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptor, Cannabinoid, CB2/agonists ; Receptor, Cannabinoid, CB2/antagonists & inhibitors ; Receptor, Cannabinoid, CB2/physiology ; Spinal Cord/pathology ; Thiazoles/pharmacology
Chemical Substances	A-836339 ; Bornanes ; Piperidines ; Pyrazoles ; Receptor, Cannabinoid, CB2 ; SR 144528 ; Thiazoles ; rimonabant (RML78EN3XE)
Language	English
Publishing date	2009-02-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	196739-3
ISSN	1873-7544 ; 0306-4522
ISSN (online)	1873-7544
ISSN	0306-4522
DOI	10.1016/j.neuroscience.2008.11.015
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Article ; Online: A selective α2 B adrenoceptor agonist (A-1262543) and duloxetine modulate nociceptive neurones in the medial prefrontal cortex, but not in the spinal cord of neuropathic rats.

Chu, K L / Xu, J / Frost, J / Li, L / Gomez, E / Dart, M J / Jarvis, M F / Meyer, M D / McGaraughty, S

European journal of pain (London, England)

2015 Volume 19, Issue 5, Page(s) 649–660

Abstract: Background: The noradrenergic system contributes to pain modulation, but the roles of its specific adrenoceptors are still being defined. We have identified a novel, potent (rat EC50 = 4.3 nM) and selective α2B receptor agonist, A-1262543, to further ... ...

Abstract	Background: The noradrenergic system contributes to pain modulation, but the roles of its specific adrenoceptors are still being defined. We have identified a novel, potent (rat EC50 = 4.3 nM) and selective α2B receptor agonist, A-1262543, to further explore this adrenoceptor subtype's contribution to pathological nociception. Methods: Systemic administration of A-1262543 (1-10 mg/kg, intraperitoneal) dose-dependently attenuated mechanical allodynia in animals with a spinal nerve ligation injury. To further explore its mechanism of action, the activity of nociceptive neurones in the spinal cord and medial prefrontal cortex (mPFC) were examined after injection of 3 mg/kg of A-1262543 (intravenous, i.v.). These effects were compared with duloxetine (3 mg/kg, i.v.), a dual noradrenaline (NA) and serotonin (5-HT) reuptake inhibitor. Results: Systemic administration of A-1262543 or duloxetine did not alter the spontaneous or evoked firing of spinal wide dynamic range and nociceptive-specific neurones in the neuropathic rats, indicating that neither compound engaged spinal, peripheral or descending pathways. In contrast to the lack of effect on spinal neurones, both A-1262543 and duloxetine reduced the evoked and spontaneous firing of 'pain-responsive' (PR) neurones in the mPFC. Duloxetine, but not A-1262543, also inhibited the firing of pain non-responsive (nPR) neurones in the mPFC probably reflecting duloxetine's contribution to modulating non-pain endpoints. Conclusions: These data highlight that activation of the α2B adrenoceptor as well as inhibiting NA and 5-HT reuptake can result in modulating the ascending nociceptive system, and in particular, dampening the firing of PR neurones in the mPFC.
MeSH term(s)	Adrenergic Uptake Inhibitors/therapeutic use ; Adrenergic alpha-Agonists/therapeutic use ; Aniline Compounds/therapeutic use ; Animals ; Behavior, Animal/drug effects ; Dose-Response Relationship, Drug ; Duloxetine Hydrochloride/therapeutic use ; Electrophysiological Phenomena/drug effects ; HEK293 Cells ; Humans ; Imidazolines/therapeutic use ; Male ; Neuralgia/drug therapy ; Neurons/drug effects ; Nociceptors/drug effects ; Prefrontal Cortex/drug effects ; Rats ; Rats, Sprague-Dawley ; Receptors, Adrenergic, alpha-2/drug effects ; Receptors, Adrenergic, alpha-2/genetics ; Spinal Cord/drug effects ; Spinal Nerves/injuries
Chemical Substances	A-1262543 ; Adrenergic Uptake Inhibitors ; Adrenergic alpha-Agonists ; Aniline Compounds ; Imidazolines ; Receptors, Adrenergic, alpha-2 ; Duloxetine Hydrochloride (9044SC542W)
Language	English
Publishing date	2015-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1390424-3
ISSN	1532-2149 ; 1090-3801
ISSN (online)	1532-2149
ISSN	1090-3801
DOI	10.1002/ejp.586
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Article: [Left ventricular function in acute myocardial infarction with bundle branch block--value of radionuclide angiocardiography].

Gao, B X / Zhang, J L / Chu, K L

Zhonghua xin xue guan bing za zhi

1986 Volume 14, Issue 6, Page(s) 333–5, 380–1

MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Bundle-Branch Block/diagnostic imaging ; Bundle-Branch Block/etiology ; Bundle-Branch Block/physiopathology ; Female ; Heart/diagnostic imaging ; Heart/physiopathology ; Heart Ventricles ; Humans ; Male ; Middle Aged ; Myocardial Infarction/complications ; Myocardial Infarction/diagnostic imaging ; Myocardial Infarction/physiopathology ; Prognosis ; Radionuclide Imaging
Language	Chinese
Publishing date	1986-12
Publishing country	China
Document type	Journal Article
ZDB-ID	603425-1
ISSN	0253-3758
ISSN	0253-3758
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Article: Effects of A-134974, a novel adenosine kinase inhibitor, on carrageenan-induced inflammatory hyperalgesia and locomotor activity in rats: evaluation of the sites of action.

McGaraughty, S / Chu, K L / Wismer, C T / Mikusa, J / Zhu, C Z / Cowart, M / Kowaluk, E A / Jarvis, M F

The Journal of pharmacology and experimental therapeutics

2001 Volume 296, Issue 2, Page(s) 501–509

Abstract: The present study investigated 1) antihyperalgesic actions of a novel and selective adenosine kinase (AK) inhibitor, A-134974 (IC(50) = 60 pM), in the carrageenan model of thermal hyperalgesia; 2) effects of A-134974 on locomotor activity; and 3) ... ...

Abstract	The present study investigated 1) antihyperalgesic actions of a novel and selective adenosine kinase (AK) inhibitor, A-134974 (IC(50) = 60 pM), in the carrageenan model of thermal hyperalgesia; 2) effects of A-134974 on locomotor activity; and 3) relative contributions of supraspinal, spinal, and peripheral sites to the actions of A-134974. Systemic A-134974 (i.p.) dose dependently reduced hyperalgesia (ED(50) = 1 micromol/kg) and at higher doses, reduced locomotor activity (ED(50) = 16 micromol/kg). Administration of A-134974 intrathecally (i.t.) was more potent (ED(50) = 6 nmol) at producing antihyperalgesia than delivering the compound by intracerebralventricular (ED(50) = 100 nmol, i.c.v.) or intraplantar (ED(50) >300 nmol) routes. In contrast, i.c.v. administration of A-134974 was more effective in reducing locomotor activity than i.t. administration (ED(50) values were 1 and >100 nmol, respectively). Increasing the pretreatment time for i.t.-delivered A-134974 caused a greater reduction in locomotor activity (ED(50) = 10 nmol). This was due to diffusion of A-134974 (i.t.) to supraspinal sites. The antihyperalgesic effects of systemic A-134974 were antagonized by the adenosine receptor antagonist theophylline (THEO, 30-500 nmol) administered i.t., but not i.c.v. In the locomotor assay, i.t.-injected THEO did not antagonize hypomobility caused by systemic or i.t. administration of A-134974. However, i.c.v. infusion of THEO did block the hypomotive actions of i.c.v.-, i.t.-, and i.p.-administered A-134974. These data demonstrate that the novel AK inhibitor A-134974 potently reduces thermal hyperalgesia primarily through interactions with spinal sites, whereas its ability to depress locomotor activity is predominantly mediated by supraspinal sites.
MeSH term(s)	Adenosine Kinase/antagonists & inhibitors ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/administration & dosage ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Carrageenan ; Central Nervous System/drug effects ; Enzyme Inhibitors/administration & dosage ; Enzyme Inhibitors/pharmacology ; Hyperalgesia/chemically induced ; Hyperalgesia/prevention & control ; Inflammation/chemically induced ; Inflammation/prevention & control ; Injections, Intraventricular ; Injections, Spinal ; Male ; Motor Activity/drug effects ; Nucleosides/pharmacology ; Peripheral Nervous System/drug effects ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/drug effects
Chemical Substances	A 134974 ; Anti-Inflammatory Agents, Non-Steroidal ; Enzyme Inhibitors ; Nucleosides ; Carrageenan (9000-07-1) ; Adenosine Kinase (EC 2.7.1.20)
Language	English
Publishing date	2001-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
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Article: A-134974: a novel adenosine kinase inhibitor, relieves tactile allodynia via spinal sites of action in peripheral nerve injured rats.

Zhu, C Z / Mikusa, J / Chu, K L / Cowart, M / Kowaluk, E A / Jarvis, M F / McGaraughty, S

Brain research

2001 Volume 905, Issue 1-2, Page(s) 104–110

Abstract: Extracellular levels of adenosine (ADO) can be raised through inhibition of adenosine kinase (AK), a primary metabolic enzyme for ADO. AK inhibitors have shown antinociceptive activity in a variety of animal models of nociception. The present study ... ...

Abstract	Extracellular levels of adenosine (ADO) can be raised through inhibition of adenosine kinase (AK), a primary metabolic enzyme for ADO. AK inhibitors have shown antinociceptive activity in a variety of animal models of nociception. The present study investigated the antinociceptive actions of a novel and selective AK inhibitor, A-134974 (IC(50)=60 pM), in a rat model of neuropathic pain (ligations of the L5/L6 spinal nerves) and explored the relative contributions of supraspinal, spinal and peripheral sites to the actions of A-134974. Systemic A-134974 dose-dependently reduced tactile allodynia (ED(50)=5 micromol/kg, i.p.) for up to 2 h. Fall latencies in the rotorod test of motor coordination were unaffected by systemic administration of A-134974 (at doses up to 30 micromol/kg, i.p.). Administration of A-134974 intrathecally (i.t.) was more potent (ED(50)=10 nmol) in relieving tactile allodynia than delivering the compound by intracerebroventricular (ED(50)>100 nmol, i.c.v.) or intraplantar (ED(50)>500 nmol) routes suggesting that spinal sites of action are the primary contributors to the anti-allodynic action of A-134974. The anti-allodynic effects of systemic A-134974 (10 micromol/kg, i.p.) were antagonized by the non-selective ADO receptor antagonist, theophylline (30-500 nmol) administered i.t. These data demonstrate that the novel AK inhibitor A-134974 potently reduces tactile allodynia through interactions with spinal sites and adds to the growing evidence that AK inhibitors may be useful as analgesic agents in a broad spectrum of pain states.
MeSH term(s)	Adenosine Kinase/antagonists & inhibitors ; Adenosine Kinase/metabolism ; Animals ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Hyperalgesia/drug therapy ; Hyperalgesia/metabolism ; Hyperalgesia/physiopathology ; Male ; Nerve Crush/adverse effects ; Nociceptors/drug effects ; Nociceptors/metabolism ; Nociceptors/physiopathology ; Nucleosides/pharmacology ; Pain/drug therapy ; Pain/metabolism ; Pain/physiopathology ; Pain Measurement/drug effects ; Peripheral Nervous System Diseases/drug therapy ; Peripheral Nervous System Diseases/metabolism ; Peripheral Nervous System Diseases/physiopathology ; Phosphodiesterase Inhibitors/pharmacology ; Physical Stimulation/adverse effects ; Posterior Horn Cells/drug effects ; Posterior Horn Cells/metabolism ; Rats ; Rats, Sprague-Dawley ; Theophylline/pharmacology
Chemical Substances	A 134974 ; Enzyme Inhibitors ; Nucleosides ; Phosphodiesterase Inhibitors ; Theophylline (C137DTR5RG) ; Adenosine Kinase (EC 2.7.1.20)
Language	English
Publishing date	2001-06-29
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/s0006-8993(01)02512-4
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Article: Risk stratification with low-level exercise testing 2 weeks after acute myocardial infarction.

Weld, F M / Chu, K L / Bigger, J T / Rolnitzky, L M

Circulation

1981 Volume 64, Issue 2, Page(s) 306–314

Abstract: We enrolled 250 patients with acute myocardial infarction after they had been discharged from the cardiac intensive care unit. Among 236 patients who performed a low-level exercise test just before hospital discharge, 52 (22%) had exercise-induced ST ... ...

Abstract	We enrolled 250 patients with acute myocardial infarction after they had been discharged from the cardiac intensive care unit. Among 236 patients who performed a low-level exercise test just before hospital discharge, 52 (22%) had exercise-induced ST depression of at least 0.1 mV in ECG lead V5, 102 (43%) had ventricular arrhythmias, and 121 (51%) had an exercise capacity of shorter than 6 minutes. We used multiple logistic regression analysis to investigate the association of exercise variables with 1-year cardiac mortality. Exercise duration and ventricular premature depolarizations (VPDs) were significantly associated with 1-year mortality after acute myocardial infarction, both with and without control of the influence of other exercise variables statistically; the association of exercise-induced ST depression with 1-year cardiac mortality was not statistically significant. Standardized regression coefficients showed that the variables ranked in the following order in terms of predictive value: exercise duration, VPD frequency and ST depression. Jackknife techniques showed that multiple logistic regression using the three exercise variables was highly accurate in predicting 1-year mortality.
MeSH term(s)	Acute Disease ; Arrhythmias, Cardiac/complications ; Coronary Disease/complications ; Exercise Test ; Female ; Heart Ventricles/physiopathology ; Humans ; Male ; Middle Aged ; Myocardial Infarction/complications ; Myocardial Infarction/mortality ; Myocardial Infarction/physiopathology ; Prognosis ; Risk ; Time Factors
Language	English
Publishing date	1981-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	80099-5
ISSN	1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
ISSN (online)	1524-4539
ISSN	0009-7322 ; 0069-4193 ; 0065-8499
DOI	10.1161/01.cir.64.2.306
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Article: P2X7-related modulation of pathological nociception in rats.

McGaraughty, S / Chu, K L / Namovic, M T / Donnelly-Roberts, D L / Harris, R R / Zhang, X-F / Shieh, C-C / Wismer, C T / Zhu, C Z / Gauvin, D M / Fabiyi, A C / Honore, P / Gregg, R J / Kort, M E / Nelson, D W / Carroll, W A / Marsh, K / Faltynek, C R / Jarvis, M F

Neuroscience

2007 Volume 146, Issue 4, Page(s) 1817–1828

Abstract: Growing evidence supports a role for the immune system in the induction and maintenance of chronic pain. ATP is a key neurotransmitter in this process. Recent studies demonstrate that the glial ATP receptor, P2X7, contributes to the modulation of ... ...

Abstract	Growing evidence supports a role for the immune system in the induction and maintenance of chronic pain. ATP is a key neurotransmitter in this process. Recent studies demonstrate that the glial ATP receptor, P2X7, contributes to the modulation of pathological pain. To further delineate the endogenous mechanisms that are involved in P2X7-related antinociception, we utilized a selective P2X7 receptor antagonist, A-438079, in a series of in vivo and in vitro experiments. Injection of A-438079 (10-300 micromol/kg, i.p.) was anti-allodynic in three different rat models of neuropathic pain and it attenuated formalin-induced nocifensive behaviors. Using in vivo electrophysiology, A-438079 (80 micromol/kg, i.v.) reduced noxious and innocuous evoked activity of different classes of spinal neurons (low threshold, nociceptive specific, wide dynamic range) in neuropathic rats. The effects of A-438079 on evoked firing were diminished or absent in sham rats. Spontaneous activity of all classes of spinal neurons was also significantly reduced by A-438079 in neuropathic but not sham rats. In vitro, A-438079 (1 microM) blocked agonist-induced (2,3-O-(4-benzoylbenzoyl)-ATP, 30 microM) current in non-neuronal cells taken from the vicinity of the dorsal root ganglia. Furthermore, A-438079 dose-dependently (0.3-3 microM) decreased the quantity of the cytokine, interleukin-1beta, released from peripheral macrophages. Thus, ATP, acting through the P2X7 receptor, exerts a wide-ranging influence on spinal neuronal activity following a chronic injury. Antagonism of the P2X7 receptor can in turn modulate central sensitization and produce antinociception in animal models of pathological pain. These effects are likely mediated through immuno-neural interactions that affect the release of endogenous cytokines.
MeSH term(s)	Action Potentials/drug effects ; Adenosine Triphosphate/analogs & derivatives ; Adenosine Triphosphate/pharmacology ; Analgesics/pharmacology ; Analgesics/therapeutic use ; Animals ; Astrocytoma ; Behavior, Animal/drug effects ; Cell Line, Tumor ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Ganglia, Spinal ; Humans ; Interleukin-1beta/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Neurons ; Pain Measurement/methods ; Purinergic P2 Receptor Agonists ; Purinergic P2 Receptor Antagonists ; Pyridines/pharmacology ; Pyridines/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Receptors, Purinergic P2/physiology ; Receptors, Purinergic P2X7 ; Sciatica/drug therapy ; Sciatica/metabolism ; Sciatica/physiopathology ; Tetrazoles/pharmacology ; Tetrazoles/therapeutic use ; Time Factors
Chemical Substances	3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine ; Analgesics ; Interleukin-1beta ; P2RX7 protein, human ; P2rx7 protein, mouse ; P2rx7 protein, rat ; Purinergic P2 Receptor Agonists ; Purinergic P2 Receptor Antagonists ; Pyridines ; Receptors, Purinergic P2 ; Receptors, Purinergic P2X7 ; Tetrazoles ; 3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate (4P5DXU1F8Q) ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2007-06-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	196739-3
ISSN	1873-7544 ; 0306-4522
ISSN (online)	1873-7544
ISSN	0306-4522
DOI	10.1016/j.neuroscience.2007.03.035
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Article: Blockade of mGluR1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A-841720, a novel non-competitive mGluR1 receptor antagonist.

El-Kouhen, O / Lehto, S G / Pan, J B / Chang, R / Baker, S J / Zhong, C / Hollingsworth, P R / Mikusa, J P / Cronin, E A / Chu, K L / McGaraughty, S P / Uchic, M E / Miller, L N / Rodell, N M / Patel, M / Bhatia, P / Mezler, M / Kolasa, T / Zheng, G Z /

Fox, G B / Stewart, A O / Decker, M W / Moreland, R B / Brioni, J D / Honore, P

British journal of pharmacology

2006 Volume 149, Issue 6, Page(s) 761–774

Abstract: Background and purpose: To further assess the clinical potential of the blockade of metabotropic glutamate receptors (mGluR1) for the treatment of pain.: Experimental approach: We characterized the effects of A-841720, a novel, potent and non- ... ...

Abstract	Background and purpose: To further assess the clinical potential of the blockade of metabotropic glutamate receptors (mGluR1) for the treatment of pain. Experimental approach: We characterized the effects of A-841720, a novel, potent and non-competitive mGluR1 antagonist in models of pain and of motor and cognitive function. Key results: At recombinant human and native rat mGluR1 receptors, A-841720 inhibited agonist-induced calcium mobilization, with IC50 values of 10.7+/-3.9 and 1.0 +/- 0.2 nM, respectively, while showing selectivity over other mGluR receptors, in addition to other neurotransmitter receptors, ion channels, and transporters. Intraperitoneal injection of A-841720 potently reduced complete Freund's adjuvant-induced inflammatory pain (ED50 = 23 micromol kg(-1)) and monoiodoacetate-induced joint pain (ED50 = 43 micromol kg(-1)). A-841720 also decreased mechanical allodynia observed in both the sciatic nerve chronic constriction injury and L5-L6 spinal nerve ligation (SNL) models of neuropathic pain (ED50 = 28 and 27 micromol kg(-1), respectively). Electrophysiological studies demonstrated that systemic administration of A-841720 in SNL animals significantly reduced evoked firing in spinal wide dynamic range neurons. Significant motor side effects were observed at analgesic doses and A-841720 also impaired cognitive function in the Y-maze and the Water Maze tests. Conclusions and implications: The analgesic effects of a selective mGluR1 receptor antagonist are associated with motor and cognitive side effects. The lack of separation between efficacy and side effects in pre-clinical models indicates that mGluR1 antagonism may not provide an adequate therapeutic window for the development of such antagonists as novel analgesic agents in humans.
MeSH term(s)	Analgesia ; Animals ; Cells, Cultured ; Cognition/drug effects ; Excitatory Amino Acid Antagonists/pharmacology ; Fluorescence ; Heterocyclic Compounds, 3-Ring/pharmacology ; Humans ; Male ; Motor Activity/drug effects ; Rats ; Rats, Sprague-Dawley ; Receptors, Metabotropic Glutamate/antagonists & inhibitors
Chemical Substances	A-841720 ; Excitatory Amino Acid Antagonists ; Heterocyclic Compounds, 3-Ring ; Receptors, Metabotropic Glutamate ; metabotropic glutamate receptor type 1
Language	English
Publishing date	2006-11
Publishing country	England
Document type	Journal Article
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1038/sj.bjp.0706877
Database	MEDical Literature Analysis and Retrieval System OnLINE

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