Preview

Phenylglycine derivatives as antagonists of group III metabotropic glutamate receptors expressed on neonatal rat primary afferent terminals

Powerful Essays
Open Document
Open Document
6437 Words
Grammar
Grammar
Plagiarism
Plagiarism
Writing
Writing
Score
Score
Phenylglycine derivatives as antagonists of group III metabotropic glutamate receptors expressed on neonatal rat primary afferent terminals
British Journal of Pharmacology (2003) 139, 1523–1531

& 2003 Nature Publishing Group All rights reserved 0007 – 1188/03 $25.00 www.nature.com/bjp Phenylglycine derivatives as antagonists of group III metabotropic glutamate receptors expressed on neonatal rat primary afferent terminals 1

Jacqueline C. Miller, 1Patrick A. Howson, 1Stuart J. Conway, 1Richard V. Williams,
Barry P. Clark & *,1David E. Jane

2

1

Department of Pharmacology, School of Medical Sciences, Bristol BS8 1TD and 2Eli Lilly and Co., Erl Wood Manor,
Windlesham, Surrey GU20 6PH

Keywords:
Abbreviations:

1 Three novel phenylglycine analogues; (RS)-a-methyl-3-chloro-4-phosphonophenylglycine
(UBP1110), (RS)-a-methyl-3-methoxy-4-phosphonophenylglycine (UBP1111) and (RS)-a-methyl-3methyl-4-phosphonophenylglycine (UBP1112) antagonised the depression of the fast component of the dorsal root-evoked ventral root potential induced by (S)-AP4 with apparent KD values of:
7.472.3, 5.470.6 and 5.170.3 mm (all n ¼ 3), respectively.
2 A Schild analysis of the antagonism of (S)-AP4 induced depression of synaptic transmission by
UBP1112 revealed a pA2 value of 5.3 and a slope of 0.8170.26 (n ¼ 9).
3 None of the phenylglycines tested were potent antagonists of responses mediated by group II mGlu receptors (apparent KD values 4480 mm). UBP1112 when tested at a concentration of 1 mm had little or no activity on (S)-3,5-DHPG-, NMDA-, AMPA- or kainate-induced responses on motoneurones.
4 UBP1110, UBP1111 and UBP1112 are at least 100-fold selective for group III over group I and II mGlu receptors expressed in the spinal cord making them the most potent, selective, antagonists yet tested at (S)-AP4 sensitive receptors in the spinal cord.
British Journal of Pharmacology (2003) 139, 1523–1531. doi:10.1038/sj.bjp.0705377
Neonatal rat spinal cord; phenylglycine; mGlu receptors; antagonist; mGlu8; UBP1110; UBP1111; UBP1112
(1S,3S)-ACPD, (1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid;



References: AGHAJANIAN, G.K. & MAREK, G.J. (2000). Serotonin model of HOWSON, P.A (1997). (S)-Homo-AMPA, a specific agonist at the mGlu6 subtype of metabotropic glutamic acid receptors (2001). Immunoreactivity for the group III metabotropic glutamate receptor subtype mGluR4a in the superficial laminae of the rat BAGUST, J. (1993). The spinal cord as an in vitro preparation. (1997). Metabotropic glutamate receptor antagonists, like GABAB antagonists potentiate dorsal root-evoked excitatory CARTMELL, J. & SCHOEPP, D.D. (2000). Regulation of neurotransmitter release by metabotropic glutamate receptors. J. Neurochem., 75, 889 – 907. CHAPMAN, A.G., NANAN, K., YIP, P. & MELDRUM, B.S. (1999). CONN, P.J. & PIN, J.P. (1997). Pharmacology and functions of metabotropic glutamate receptors (2000). Pharmacological characterization of the rat metabotropic glutamate receptor type 8a revealed strong similarities and slight differences with the type 4a receptor NICOLETTI, F. & FLOR, P.J. (1999). (RS)-4-phosphonophenylglycinc a potent and selective group III metabotropic glutamate receptor agonist is anticonvulsant and neuroprotective in vivo. J. Pharmacol. Exp. Ther., 289, 1678 – 1687. HOWSON, P.A. & JANE, D.E. (2002). A comparison of group III metabotropic glutamate receptor agonists and the ability of JANE, D.E., THOMAS, N.K., TSE, H-W. & WATKINS, J.C. (1996). spinal cord. Neuropharmacology, 35, 1029 – 1035. MILLER, J.C., CONWAY, S.J., CLARK, B.P. & JANE, D.E. (2000). MILLER, J.C., O’NEILL, M.J. & JANE, D.E. (2001). Immunocytochemical localisation of glutamate receptor subtypes in the lumbar region of the spinal cord MILLS, C.D., JOHNSON, K.M. & HULSEBOSCH, C.E. (2002). Role of group II and group III metabotropic glutamate receptors in spinal NAKAJIMA, Y., IWAKABE, H., AKAZAWA, C., NAWA, H., SHIGEMOTO, R., MIZUNO, R. & NAKANISHI, S. (1993). Molecular characterisation of a novel retinal metabotropic glutamate receptor mGluR6 with a high agonist selectivity for L-AP4. J. Biol. Chem., 268, 11868 – 11873.

You May Also Find These Documents Helpful

  • Powerful Essays

    Toxicology of Propoxur

    • 1831 Words
    • 8 Pages

    Rang, H. P. and M. M. Dale (2012). RANG and DALE 'S Pharmacology. London, Elsevier.…

    • 1831 Words
    • 8 Pages
    Powerful Essays
  • Satisfactory Essays

    receptor, the AMPA receptor and lastly the kainate receptor. The last receptor is based off of a…

    • 659 Words
    • 3 Pages
    Satisfactory Essays
  • Satisfactory Essays

    anatomy 11.2

    • 1575 Words
    • 7 Pages

    What neurotransmitter is used in all preganglionic fibers? What is the receptor in the ganglia?…

    • 1575 Words
    • 7 Pages
    Satisfactory Essays
  • Satisfactory Essays

    Nt1310 Unit 3 Lab Report

    • 405 Words
    • 2 Pages

    5. Lidocaine blocks the Na+ channels which prevents the propagation of the action potential from R1 to R2.…

    • 405 Words
    • 2 Pages
    Satisfactory Essays
  • Satisfactory Essays

    a. The binding of ACh opens ion channels in the dendrites or cell body that…

    • 278 Words
    • 2 Pages
    Satisfactory Essays
  • Satisfactory Essays

    ____________ is a member of xanthine family that is used in therapy for respiratory diseases such as Asthma.…

    • 810 Words
    • 4 Pages
    Satisfactory Essays
  • Better Essays

    Dulaglutide Case Study

    • 1733 Words
    • 7 Pages

    Adult male rats received a single subcutaneous dose of 0.1 mg per kg dulaglutide, and blood samples were collected 1,2,4 and 6 days following administration. A group of 3 monkeys received a subcutaneous dose of 0.1 mg per kg dulaglutide and blood samples were collected at 0, 2, 4, 12, 48, 72 96, 192, 240, 288 and 336 hours following administration. Samples from both animals were studies for GLP-1-Fc concentration using ELISA, utilizing antibodies that recognize the N-terminus of GLP-1-Fc and the Fc domain. Optical density of tetramethylbenzidine development was measured and concentrations of GLP-1-Fc were calculated using the four parameter algorithm (Glaesner, et al., 2010). The pharmacokinetic parameters of dulaglutide for rats and monkeys respectively were: t1/2= 38.2 hours, and 51.6 hours; Cmax = 179.7 ng/mL, and 292.2 ng/mL; Tmax= 24 hours, and 16.7 hours; Cl = 9.6 ml/h/kg, and 7.3 mL/h/kg; VD = 525.0 mL/kg, and 557.5 mL/kg; AUC0- ∞ = 10,537 and 15,207 (Glaesner, et al., 2010; Jimenez-Solem et al.,…

    • 1733 Words
    • 7 Pages
    Better Essays
  • Powerful Essays

    Your brain on food

    • 41913 Words
    • 168 Pages

    Your Brain on Food S This page intentionally left blank Your Brain on Food How Chemicals Control Your Thoughts and Feelings Gary L. Wenk, PhD Departments of Psychology and Neuroscience and Molecular Virology, Immunology and Medical Genetics The Ohio State University Columbus, OH 1 2010 1 Oxford University Press, Inc., publishes works that further Oxford University’s objective of excellence in research, scholarship, and education. Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With offices in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam Copyright © 2010 by Oxford University Press Published by Oxford University Press, Inc.…

    • 41913 Words
    • 168 Pages
    Powerful Essays
  • Satisfactory Essays

    1. Heart failure (HF) is a syndrome that involves dysfunction of the cardiac muscle, it occurs with “any of disorders that damage or overwork the heart muscle” (Karch, 2017 p.751). Some of the disorders that may lead to HF are: coronary artery disease, cardiomyopathy, hypertension, and valvular heart disease (Karch, 2017). What ends up happening as a result of these disorders, is that the heart muscle cannot effectively pump blood throughout the vascular system (Karch, 2017). In left-sided heart failure, the “blood backs up into the lungs which leads to pulmonary vessel congestion and fluid leakage into the alveoli and lung tissue” (Karch, 2017 p.752). In right-sided failure, the blood backs up in the venous system, which may lead to liver congestion and edema of the legs and feet (Karch, 2017).…

    • 405 Words
    • 2 Pages
    Satisfactory Essays
  • Satisfactory Essays

    Astrocytes play a role in the reuptake of neurotransmitters. They also have a role in providing activity dependent metabolic support to neurons. This is done via the lactate shuttle. When an action potential is fired, some presynaptic neurons release glutamate into the synapse. The glutamate response is eventually terminated by the reuptake of glutamate in astrocytes. Within the astrocyte, the glutamate is converted to glutamine. Then, the glutamine is transported from the astrocyte to the presynaptic cell. In the presynaptic cell, the glutamine is converted back to glutamate,…

    • 509 Words
    • 3 Pages
    Satisfactory Essays
  • Good Essays

    Amphetamines Essay

    • 1449 Words
    • 6 Pages

    Amphetamines are substrates for carriers linked with the uptake of the biogenic amines dopamine (DA), norepinephrine (NE), and serotonin (5-HT) (Kehr et al., 2011). The dopamine and the serotonin release from storage vesicles, avoid the uptake into vesicles, and making them more freely available for inverse transport. Both dopamine and the serotonin are promoted by amphetamines. An increased neurotransmission of dopamine occurs by the acute action of the amphetamines. Amphetamines are also increased because of the release of glutamate. Glutamate possibly contributes to the neurotoxicity profiles of these drugs (Kehr et al.,…

    • 1449 Words
    • 6 Pages
    Good Essays
  • Good Essays

    Brinking Water Case Study

    • 328 Words
    • 2 Pages

    They have used of three neurotransmitter ACh, 5-HT and GABA; it seems use of ACh is Logical, but what about 5-HT and GABA? Especial about the 5-HT with considering the verity of excitatory…

    • 328 Words
    • 2 Pages
    Good Essays
  • Good Essays

    Glutamates: A Summary

    • 82 Words
    • 1 Page

    “NMDA receptor antagonist work by regulating the activity of glutamate. Glutamate is an important neurotransmitter in the brain involved in the learning and memory process”(alz.org, 2017). “With alzheimer’s disease, cells can produce too much glutamate” (webmd.com, 2017). Too much glutamate can result in nerve cells receiving an excess amount of calcium. This excess of calcium can quicken the process of cell damage. Memantine is a medication associated with this drug class that is used to “help partially block NMDA receptors” (alz.org, 2017).…

    • 82 Words
    • 1 Page
    Good Essays
  • Good Essays

    Botulinum neurotoxins (BoNTs) are the most potent toxins known and the causative agent of botulism. Their exceptional toxicity is caused by the highly efficient inhibition of neurotransmitter release at the neuromuscular junction. High affinity binding of BoNTs is mediated by the simultaneous interaction with lipid embedded synaptic vesicle proteins and gangliosides the presynaptic membrane according to the well-established dual-receptor binding model. One peculiarity that is especially pronounced in BoNT serotypes B, DC, and G – which all use synaptotagmin as a common protein-receptor – is the occurrence of a distinct hydrophobic loop located between the ganglioside and protein receptor sites. Both its location and hydrophobic character have…

    • 299 Words
    • 2 Pages
    Good Essays
  • Powerful Essays

    Sodium Glutamate

    • 3335 Words
    • 14 Pages

    Therefore, Olney, Adamo and Ratner (1971, p. 294) estimate that larger numbers of adult rats after multiple MSG treatments in infancy and have consistently found that average weights of the adenohypophysis (the glandular, anterior lobe of the pituitary gland) are about one-half those of control animals. In addition, Young and Ajami (2000, pp. 892-900) argue that in infant retina and hypothalamus (a neural control centre at the base of the brain), susceptible nerve cells undergo rapid necrosis (the death of most or all of the cells in an organ) and are phagocytized (the cellular process of engulfing solid particles), degraded, and evacuated from affected areas within 24 to 48 hours after MSG treatment. Consequently, it is clearly shown that MSG may have several hostile effects on brain work possibilities. Although Arees, Mayer, Burde, Shainker and Kayes, J. (1970, p. 549) have found both the rat and mouse susceptible to MSG-induced brain damage, Olney’s at al. (1971, p. 294) study was the first report to suggest the possibility that a single subcutaneous injection of MSG may not produce neuronal necrosis in the arcuate nucleus of infant rats. Additionally, Sampson (2003, pp. 701-706) reported failure to detect brain damage in infant rats injected subcutaneously with monosodium glutamate (MSG). However, Hanon (2007) states that normal neural components can…

    • 3335 Words
    • 14 Pages
    Powerful Essays