Biotransformation of a novel positive allosteric modulator of metabotropic glutamate receptor subtype 5 contributes to seizure-like adverse events in rats involving a receptor agonism-dependent mechanism

Drug Metabolism and Disposition

Volumn 41, Issue 9, 2013, Pages 1703-1714

  Bridges, Thomas M ^a   Rook, Jerri M ^a   Noetzel, Meredith J ^a   Morrison, Ryan D ^a   Zhou, Ya ^a   Gogliotti, Rocco D ^a   Vinson, Paige N ^a   Xiang, Zixiu ^a   Jones, Carrie K ^a   Niswender, Colleen M ^a   Lindsley, Craig W ^a   Stauffer, Shaun R ^a   Conn, P Jeffrey ^a   Daniels, J Scott ^a  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 AMINOBENZOTRIAZOLE; 2 METHYL 6 (PHENYLETHYNYL)PYRIDINE; 5 [(3 FLUROPHENYL)ETHYNYL] N (3 HYDROXYCYCLOBUTYL)PICOLINAMIDE; 5 [(3 FLUROPHENYL)ETHYNYL]PICOLINIC ACID; DRUG METABOLITE; GLUTAMATE RECEPTOR AGONIST; METABOTROPIC RECEPTOR 7; METABOTROPIC RECEPTOR AGONIST; N CYCLOBUTYL 5 [(3 FLUOROPHENYL)ETHYNYL]PICOLINAMIDE; POSITIVE ALLOSTERIC MODULATOR; UNCLASSIFIED DRUG; VU 0403602;

ADVERSE OUTCOME; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; BINDING AFFINITY; BINDING SITE; BRAIN ELECTROPHYSIOLOGY; BRAIN SLICE; CONTROLLED STUDY; DOSE RESPONSE; DRUG CLEARANCE; DRUG DISPOSITION; DRUG DISTRIBUTION; DRUG EFFECT; DRUG HALF LIFE; DRUG MECHANISM; DRUG MEGADOSE; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG TRANSFORMATION; EMBRYO; HIPPOCAMPUS; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; LOW DRUG DOSE; MALE; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; PRIORITY JOURNAL; RAT; SEIZURE; SINGLE DRUG DOSE; TIME TO MAXIMUM PLASMA CONCENTRATION;

ALLOSTERIC REGULATION; ANIMALS; ASTROCYTES; BIOTRANSFORMATION; CELL LINE; CYTOCHROME P-450 ENZYME SYSTEM; HEK293 CELLS; HIPPOCAMPUS; HUMANS; LIVER; MALE; RATS; RATS, SPRAGUE-DAWLEY; RECEPTOR, METABOTROPIC GLUTAMATE 5; SEIZURES;

EID: 84882784373     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.113.052084     Document Type: Article

References (29)

1. Balani SK, Miwa GT, Gan LS, Wu JT, and Lee FW (2005) Strategy of utilizing in vitro and in vivo ADME tools for lead optimization and drug candidate selection. Curr Top Med Chem 5: 1033-1038.
2. Balani SKZ, Zhu T, Yang TJ, Liu Z, He B, and Lee FW (2002) Effective dosing regimen of 1-Aminobenzotriazole for inhibition of antipyrine clearance in rats, dogs, and monkeys. Drug Metab Dispos 30:1059-1062.
3. Conn PJ, Lindsley CW, and Jones CK (2009) Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia. Trends Pharmacol Sci 30:25-31.
4. Cosford ND, Roppe J, Tehrani L, Schweiger EJ, Seiders TJ, Chaudary A, Rao S, and Varney MA (2003) [3H]-methoxymethyl-MTEP and [3H]-methoxy-PEPy: potent and selective radioligands for the metabotropic glutamate subtype 5 (mGlu5) receptor. Bioorg Med Chem Lett 13: 351-354.
5. Gregory KJ, Dong EN, Meiler J, and Conn PJ (2011) Allosteric modulation of metabotropic glutamate receptors: structural insights and therapeutic potential. Neuropharmacology 60: 66-81.
6. Gregory KJ, Nguyen ED, Reiff SD, Squire EF, Stauffer SR, Lindsley CW, Meiler J, and Conn PJ (2013) Probing the metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulator (PAM) binding pocket: discovery of point mutations that engender a "molecular switch" in PAM pharmacology. Mol Pharmacol 83:991-1006.
7. Hammond AS, Rodriguez AL, Townsend SD, Niswender CM, Gregory KJ, Lindsley CW, and Conn PJ (2010) Discovery of a novel chemical class of mGlu(5) allosteric ligands with distinct modes of pharmacology. ACS Chem Neurosci 1:702-716.
8. Kalvass JC and Maurer TS (2002) Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery. Biopharm Drug Dispos 23:327-338.
9. Lamb JP, Engers DW, Niswender CM, Rodriguez AL, Venable DF, Conn PJ, and Lindsley CW (2011) Discovery of molecular switches within the ADX-47273 mGlu5 PAM scaffold that modulate modes of pharmacology to afford potent mGlu5 NAMs, PAMs and partial antagonists. Bioorg Med Chem Lett 21:2711-2714.
10. Lee AC, Wong RK, Chuang SC, Shin HS, and Bianchi R (2002) Role of synaptic metabotropic glutamate receptors in epileptiform discharges in hippocampal slices. J Neurophysiol 88: 1625-1633.
11. Lindsley CW (2011) Molecular switches' on mGluR allosteric ligands that modulate modes of pharmacology and/or subtype selectivity, in 7th International Metabotropic Glutamate Receptors Meeting, Taormina, Italy. Curr Neuropharmacol 9(1):36
12. Liu X, Chen C, and Smith BJ (2008) Progress in brain penetration evaluation in drug discovery and development. J Pharmacol Exp Ther 325:349-356.
13. Marek GJ, Behl B, Bespalov AY, Gross G, Lee Y, and Schoemaker H (2010) Glutamatergic (Nmethyl-D-Aspartate receptor) hypofrontality in schizophrenia: too little juice or a miswired brain? Mol Pharmacol 77:317-326.
14. Niswender CM, Johnson KA, Weaver CD, Jones CK, Xiang Z, Luo Q, Rodriguez AL, Marlo JE, de Paulis T, and Thompson AD, et al. (2008) Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4. Mol Pharmacol 74:1345-1358.
15. Noetzel MJ, Rook JM, Vinson PN, Cho HP, Days E, Zhou Y, Rodriguez AL, Lavreysen H, Stauffer SR, and Niswender CM, et al. (2012) Functional impact of allosteric agonist activity of selective positive allosteric modulators of metabotropic glutamate receptor subtype 5 in regulating central nervous system function. Mol Pharmacol 81:120-133.
16. Obach RS and Reed-Hagen AE (2002) Measurement of Michaelis constants for cytochrome P450-mediated biotransformation reactions using a substrate depletion approach. Drug Metab Dispos 30:831-837.
17. Olney JW, Newcomer JW, and Farber NB (1999) NMDA receptor hypofunction model of schizophrenia. J Psychiatr Res 33:523-533.
18. Parmentier-Batteur S, Hutson PH, Menzel K, Uslaner JM, Mattson BA, O'Brien JA, Magliaro BC, Forest T, Stump CA, and Tynebor RM, et al. (2013) Mechanism based neurotoxicity of mGlu5 positive allosteric modulators: development challenges for a promising novel antipsychotic target. Neuropharmacology, in press.
19. Rodriguez AL, Grier MD, Jones CK, Herman EJ, Kane AS, Smith RL, Williams R, Zhou Y, Marlo JE, and Days EL, et al. (2010) Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity. Mol Pharmacol 78: 1105-1123.
20. Rook JM, Noetzel MJ, Pouliot WA, Bridges TM, Vinson PN, Cho HP, Zhou Y, Gogliotti RD, Manka JT, Gregory KJ, et al. (2012) Unique signaling profiles of positive allosteric modulators of metabotropic glutamate receptor subtype 5 determine differences in in vivo activity. Biological Psychiatry 73(6):501-9.
21. Sharma S, Kedrowski J, Rook JM, Smith RL, Jones CK, Rodriguez AL, Conn PJ, and Lindsley CW (2009) Discovery of molecular switches that modulate modes of metabotropic glutamate receptor subtype 5 (mGlu5) pharmacology in vitro and in vivo within a series of functionalized, regioisomeric 2-And 5-(phenylethynyl)pyrimidines. J Med Chem 52:4103-4106.
22. Tizzano JP, Griffey KI, and Schoepp DD (1995a) Induction or protection of limbic seizures in mice by mGluR subtype selective agonists. Neuropharmacology 34:1063-1067.
23. Tizzano JP, Griffey KI, and Schoepp DD (1995b) Receptor subtypes linked to metabotropic glutamate receptor agonist-mediated limbic seizures in mice. Ann N Y Acad Sci 765:230-235, discussion 248.
24. Tsai G and Coyle JT (2002) Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol 42:165-179.
25. Vinson PN and Conn PJ (2012) Metabotropic glutamate receptors as therapeutic targets for schizophrenia. Neuropharmacology 62:1461-1472.
26. Williams R, Manka JT, Rodriguez AL, Vinson PN, Niswender CM, Weaver CD, Jones CK, Conn PJ, Lindsley CW, and Stauffer SR (2011) Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold. Bioorg Med Chem Lett 21:1350-1353.
27. Wong RK, Bianchi R, Chuang SC, and Merlin LR (2005) Group I mGluR-induced epileptogenesis: distinct and overlapping roles of mGluR1 and mGluR5 and implications for antiepileptic drug design. Epilepsy Curr 5:63-68.
28. Wood MR, Hopkins CR, Brogan JT, Conn PJ, and Lindsley CW (2011) "Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology. Biochemistry 50: 2403-2410.
29. Zhao W, Bianchi R, Wang M, and Wong RK (2004) Extracellular signal-regulated kinase 1/2 is required for the induction of group I metabotropic glutamate receptor-mediated epileptiform discharges. J Neurosci 24:76-84.