AZD9272 and AZD2066: Selective and highly central nervous system penetrant mGluR5 antagonists characterized by their discriminative effects

Journal of Pharmacology and Experimental Therapeutics

Volumn 350, Issue 2, 2014, Pages 212-222

  Swedberg, Michael D B ^a,b   Raboisson, Patrick ^a,c  

^a ASTRAZENECA R AND D   (Sweden)

^b Swedberg Preclinical Partner AB (Inc)   (Sweden)

^c Galderma R and D   (France)

Author keywords

[No Author keywords available]

Indexed keywords

3 FLUORO 5 (3 (5 FLUOROPYRIDIN 2 YL) 1,2,4 OXADIAZOL 5 YL)BENZONITRILE; 3 [(2 METHYL 4 THIAZOLYL)ETHYNYL]PYRIDINE; 4 [5 (1 (5 (3 CHLOROPHENYL)ISOXAZOL 3 YL)ETHOXY) 4 METHYL 4H 1,2,4 TRIAZOL 3 YL]PYRIDINE; AZD2066; AZD9272; CHLORDIAZEPOXIDE; COCAINE; DRONABINOL; FENOBAM; METABOTROPIC RECEPTOR 5; METABOTROPIC RECEPTOR ANTAGONIST; PHENCYCLIDINE; UNCLASSIFIED DRUG;

ANALGESIA; ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DOSE RESPONSE; DRUG DEVELOPMENT; DRUG DISCRIMINATION; DRUG DISCRIMINATION TEST; DRUG HALF LIFE; DRUG MECHANISM; DRUG PENETRATION; MALE; NONHUMAN; PRIORITY JOURNAL; RAT; RESPONSE TIME; TRAINING;

ANIMALS; DISCRIMINATION LEARNING; DOSE-RESPONSE RELATIONSHIP, DRUG; DRONABINOL; ISOXAZOLES; MALE; OXADIAZOLES; PYRIDINES; RATS; RATS, WISTAR; RECEPTOR, METABOTROPIC GLUTAMATE 5; THIAZOLES; TRIAZOLES;

EID: 84905037094     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.114.215137     Document Type: Article

References (60)

1. 11C]AZD9272. Nucl Med Biol 40: 547-553.
2. Aniline O and Pitts FN, Jr (1982) Phencyclidine (PCP): a review and perspectives. Crit Rev Toxicol 10:145-177.
3. Ator NA and Griffiths RR (1983) Lorazepam and pentobarbital drug discrimination in baboons: cross-drug generalization and interaction with Ro 15-1788. J Pharmacol Exp Ther 226:776-782.
4. Bey T and Patel A (2007) Phencyclidine intoxication and adverse effects: a clinical and pharmacological review of an illicit drug. Cal J Emerg Med 8:9-14.
5. Bondareva TS, Young R, and Glennon RA (2002) Central stimulants as discriminative stimuli. Asymmetric generalization between (-)ephedrine and S(+)methamphetamine. Pharmacol Biochem Behav 74:157-162.
6. Busse CS, Brodkin J, Tattersall D, Anderson JJ, Warren N, Tehrani L, Bristow LJ, Varney MA, and Cosford ND (2004) The behavioral profile of the potent and selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]pyridine (MTEP) in rodent models of anxiety. Neuropsychopharmacology 29:1971-1979.
7. Carter LP, Griffiths RR, Suess PE, Casada JH, Wallace CL, and Roache JD (2007) Relative abuse liability of indiplon and triazolam in humans: a comparison of psychomotor, subjective, and cognitive effects. J Pharmacol Exp Ther 322:749-759.
8. Chapman AG and Meldrum BS (1989) Non-competitive N-methyl-D-aspartate antagonists protect against sound-induced seizures in DBA/2 mice. Eur J Pharmacol 166:201-211.
9. Chapman AG, Graham JL, Patel S, and Meldrum BS (1991a) Anticonvulsant activity of two orally active competitive N-methyl-D-aspartate antagonists, CGP 37849 and CGP 39551, against sound-induced seizures in DBA/2 mice and photically induced myoclonus in Papio papio. Epilepsia 32:578-587.
10. Chapman AG, Smith SE, and Meldrum BS (1991b) The anticonvulsant effect of the non-NMDA antagonists, NBQX and GYKI 52466, in mice. Epilepsy Res 9:92-96.
11. Colpaert FC, Niemegeers CJE, and Janssen PAJ (1980) Factors regulating drug cue sensitivity: limits of discriminability and the role of a progressively decreasing training dose in fentanyl-saline discrimination. J Pharmacol Exp Ther 212:474-480.
12. Conn PJ and Pin J-P (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205-237.
13. Domenici MR, Azad SC, Marsicano G, Schierloh A, Wotjak CT, Dodt HU, Zieglgänsberger W, Lutz B, and Rammes G (2006) Cannabinoid receptor type 1 located on presynaptic terminals of principal neurons in the forebrain controls glutamatergic synaptic transmission. J Neurosci 26:5794-5799.
14. D'Souza DC, Perry E, MacDougall L, Ammerman Y, Cooper T, Wu T, Braley G, Gueorguieva R, and Krystal JH (2004) The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 29:1558-1572.
15. Ferrara SD, Giorgetti R, Zancaner S, Orlando R, Tagliabracci A, Cavarzeran F, and Palatini P (1999) Effects of single dose of gamma-hydroxybutyric acid and lorazepam on psychomotor performance and subjective feelings in healthy volunteers. Eur J Clin Pharmacol 54:821-827.
16. Friedmann CTH, Davis LJ, Ciccone PE, and Rubin RT (1980) Phase II double-blind controlled study of a new anxiolytic, Fenobam (McN-3377) vs placebo. Curr Therapeutic Res 27:144-151.
17. Gasparini F, Lingenhöhl K, Stoehr N, Flor PJ, Heinrich M, Vranesic I, Biollaz M, Allgeier H, Heckendorn R, and Urwyler S, et al. (1999) 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 38:1493-1503.
18. Griffiths RR, McLeod DR, Bigelow GE, Liebson IA, Roache JD, and Nowowieski P (1984) Comparison of diazepam and oxazepam: preference, liking and extent of abuse. J Pharmacol Exp Ther 229:501-508.
19. Hayes BA and Balster RL (1985) Anticonvulsant properties of phencyclidine-like drugs in mice. Eur J Pharmacol 117:121-125.
20. Irwin S (1968) Comprehensive observational assessment: Ia. A systematic, quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacology (Berl) 13:222-257.
21. Itil TM, Seaman PA, Huque M, Mukhopadhyay S, Blasucci D, Nq KT, and Ciccone PE (1978) The clinical and quantitative EEG effects and plasma levels of Fenobam (McN-3377) in subjects with anxiety: An open rising dose tolerance and efficacy study. Curr Therapeutic Res 24:708-724.
22. Järbe TUC and Swedberg MDB (1998) Discriminative stimulus functions of CNS sedative drugs assessed by drug versus drug discrimination procedures in gerbils. Psychopharmacology (Berl) 135:201-212.
23. Johanson CE, Lundahl LH, Lockhart N, and Schubiner H (2006) Intravenous cocaine discrimination in humans. Exp Clin Psychopharmacol 14:99-108.
24. Kågedal M, Cselényi Z, Nyberg S, Jönsson S, Raboisson P, Stenkrona P, Hooker AC, and Karlsson MO (2012) Non-linear mixed effects modelling of positron emission tomography data for simultaneous estimation of radioligand kinetics and occupancy in healthy volunteers. Neuroimage 61:849-856.
25. Kågedal M, Cselényi Z, Nyberg S, Raboisson P, Ståhle L, Stenkrona P, Varnäs K, Halldin C, Hooker AC, and Karlsson MO (2013) A positron emission tomography study in healthy volunteers to estimate mGluR5 receptor occupancy of AZD2066 - estimating occupancy in the absence of a reference region. Neuroimage 82:160-169.
26. Kalliomäki J, Huizar K, Kågedal M, Hägglöf B, and Schmelz M (2013) Evaluation of the effects of a metabotropic glutamate receptor 5-antagonist on electrically induced pain and central sensitization in healthy human volunteers. Eur J Pain 17:1465-1471.
27. Kelley BM, Porter JH, and Varvel SA (1995) Mianserin as a discriminative stimulus in rats: asymmetrical cross-generalization with scopolamine. Psychopharmacology (Berl) 120:491-493.
28. Keywood C, Wakefield M, and Tack J (2009) A proof-of-concept study evaluating the effect of ADX10059, a metabotropic glutamate receptor-5 negative allosteric modulator, on acid exposure and symptoms in gastro-oesophageal reflux disease. Gut 58:1192-1199.
29. Kleven MS and Koek W (1998) Discriminative stimulus properties of cocaine: enhancement by monoamine reuptake blockers. J Pharmacol Exp Ther 284:1015-1025.
30. Koek W, Woods J H, and Colpaert FC (1990) N-methyl-D-aspartate antagonism and phencyclidine-like activity: a drug discrimination analysis. J Pharmacol Exp Ther 253: 1017-1025.
31. Lapierre YD and Oyewumi LK (1982) Fenobam: another anxiolytic? Curr Therapeutic Res 31:95-101.
32. Lévénés C, Daniel H, Soubrié P, and Crépel F (1998) Cannabinoids decrease excitatory synaptic transmission and impair long-term depression in rat cerebellar Purkinje cells. J Physiol 510:867-879.
33. Lile JA, Stoops WW, Glaser PEA, Hays LR, and Rush CR (2011) Discriminative stimulus, subject-rated and cardiovascular effects of cocaine alone and in combination with aripiprazole in humans. J Psychopharmacol 25:1469-1479.
34. Mirza NR, Rodgers RJ, and Mathiasen LS (2006) Comparative cue generalization profiles of L-838, 417, SL651498, zolpidem, CL218,872, ocinaplon, bretazenil, zopiclone, and various benzodiazepines in chlordiazepoxide and zolpidem drug discrimination. J Pharmacol Exp Ther 316:1291-1299.
35. Monaghan DT, Bridges RJ, and Cotman CW (1989) The excitatory amino acid receptors: their classes, pharmacology, and distinct properties in the function of the central nervous system. Annu Rev Pharmacol Toxicol 29:365-402.
36. Movsesyan VA, O'Leary DM, Fan L, Bao W, Mullins PGM, Knoblach SM, and Faden AI (2001) mGluR5 antagonists 2-methyl-6-(phenylethynyl)-pyridine and (E)-2-methyl-6-(2-phenylethenyl)-pyridine reduce traumatic neuronal injury in vitro and in vivo by antagonizing N-methyl-D-aspartate receptors. J Pharmacol Exp Ther 296:41-47.
37. Muly EC, Maddox M, and Smith Y (2003) Distribution of mGluR1alpha and mGluR5 immunolabeling in primate prefrontal cortex. J Comp Neurol 467:521-535.
38. Nader MA, Grant KA, Davies HML, Mach RH, and Childers SR (1997) The reinforcing and discriminative stimulus effects of the novel cocaine analog 2beta-propanoyl-3beta-(4-tolyl)-tropane in rhesus monkeys. J Pharmacol Exp Ther 280: 541-550.
39. Nicholson KL, Mansbach RS, Menniti FS, and Balster RL (2007) The phencyclidine-like discriminative stimulus effects and reinforcing properties of the NR2B-selective N-methyl-D-aspartate antagonist CP-101 606 in rats and rhesus monkeys. Behav Pharmacol 18:731-743.
40. O'Leary DM, Movsesyan V, Vicini S, and Faden AI (2000) Selective mGluR5 antagonists MPEP and SIB-1893 decrease NMDA or glutamate-mediated neuronal toxicity through actions that reflect NMDA receptor antagonism. Br J Pharmacol 131:1429-1437.
41. Pecknold JC, McClure DJ, and Appeltauber L (1980) Fenobam in anxious outpatients. Curr Therapeutic Res 27:119-123.
42. Pecknold JC, McClure DJ, Appeltauer L, Wrzesinski L, and Allan T (1982) Treatment of anxiety using fenobam (a nonbenzodiazepine) in a double-blind standard (diazepam) placebo-controlled study. J Clin Psychopharmacol 2:129-133.
43. Porter RHP, Jaeschke G, Spooren W, Ballard TM, Büttelmann B, Kolczewski S, Peters J-U, Prinssen E, Wichmann J, and Vieira E, et al. (2005) Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity. J Pharmacol Exp Ther 315:711-721.
44. Raboisson P, Breitholtz-Emanuelsson A, Dahllöf H, Edwards L, Heaton WL, Isaac M, Jarvie K, Kers A, Minidis ABE, and Nordmark A, et al (2012a) Discovery and characterization of AZD9272 and AZD6538-Two novel mGluR5 negative allosteric modulators selected for clinical development. Bioorg Med Chem Lett 22: 6974-6979.
45. Raboisson P, Kågedal M, Andersson A, Nyberg S, Cselényi Z, Farde L, Ståhle L, Karlsten R, and Jonzon B (2012b) Evaluation of the occupancy-efficacy and occupancy-CNS AES relationship of the mGluR5 antagonists AZD9272, AZD2066 and AZD2516. 14th World Congress on Pain; 2012 Aug 27-31; Milan, Italy.
46. Rall TW (1990) Hypnotics and sedatives; ethanol, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, Ed. 8th (Goodman Gilman A, Rall TW, Nies AS, and Taylor P eds) pp 244-268, Pergamon Press, New York.
47. Rohof WO, Lei A, Hirsch DP, Ny L, Astrand M, Hansen MB, and Boeckxstaens GE (2012) The effects of a novel metabotropic glutamate receptor 5 antagonist (AZD2066) on transient lower oesophageal sphincter relaxations and reflux episodes in healthy volunteers. Aliment Pharmacol Ther 35:1231-1242.
48. Schoepp D (2001) Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J Pharmacol Exp Ther 299:12-20.
49. Snedecor GW and Cochran WG (1967) Statistical Methods, pp 135-171, Iowa State University Press, Ames, IA.
50. Spooren WPJM, Gasparini F, Salt TE, and Kuhn R (2001) Novel allosteric antagonists shed light on mglu(5) receptors and CNS disorders. Trends Pharmacol Sci 22: 331-337.
51. Ståhle L, Karlsten R, Jonzon B, Eriksson B, and Kågedal M (2012) Safety Evaluation of the mGluR5 antagonists AZD9272, AZD2066 and AZD2516 in healthy volunteers and patients with neuropathic pain or major depressive disorder. 14th World Congress on Pain; 2012 Aug 27-31; Milan, Italy.
52. Swedberg MDB (2013) A proactive nonclinical drug abuse and dependence liability assessment strategy: a sponsor perspective. Behav Pharmacol 24:396-402.
53. Swedberg MDB, Ellgren M, and Raboisson P (2014) mGluR5 antagonist-induced psychoactive properties: MTEP drug discrimination, a pharmacologically selective non-NMDA effect with apparent lack of reinforcing properties. J Pharmacol Exp Ther 349:155-164.
54. Swedberg MDB, Jacobsen P, and Honoré T (1995) Anticonvulsant, anxiolytic and discriminative effects of the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX). J Pharmacol Exp Ther 274:1113-1121.
55. Swedberg MDB and Järbe TUC (1985) Drug discrimination procedures: roles of relative stimulus control in two-drug cases. Psychopharmacology (Berl) 86: 444-451.
56. Swedberg MDB and Järbe TUC (1986) Drug discrimination procedures: differential characteristics of the drug A vs drug B and the drug A vs drug B vs no drug cases. Psychopharmacology (Berl) 90:341-346.
57. Varma N, Carlson GC, Ledent C, and Alger BE (2001) Metabotropic glutamate receptors drive the endocannabinoid system in hippocampus. J Neurosci 21:RC188.
58. Varney MA, Cosford NDP, Jachec C, Rao SP, Sacaan A, Lin FF, Bleicher L, Santori EM, Flor PJ, and Allgeier H, et al. (1999) SIB-1757 and SIB-1893: selective, noncompetitive antagonists of metabotropic glutamate receptor type 5. J Pharmacol Exp Ther 290:170-181.
59. Wiley JL (1999) Cannabis: discrimination of "internal bliss"? Pharmacol Biochem Behav 64:257-260.
60. Willetts J and Balster RL (1988) The discriminative stimulus effects of N-methyl-D-aspartate antagonists in phencyclidine-trained rats. Neuropharmacology 27: 1249-1256.