Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s).
BACKGROUND
To increase subtype selectivity and provide a novel means to alter receptor function, we discovered and characterization potentiators for the metabotropic glutamate 2 receptor (mGlu2).


RESULTS
A class of 3-pyridylmethylsulfonamides (e.g., 3-MPPTS; 2,2,2-trifluoro-N-[3-(2-methoxyphenoxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide) were found to be potent, subtype-selective potentiators of human and rat mGlu2. The sulfonamides increased agonist potency in functional assays but did not displace orthosteric radiolabeled antagonist or agonist binding to cloned mGlu2 receptors. Rather, the modulators increased the affinity of most of the orthosteric agonists including glutamate, DCG-IV (2S,2'R,3'R)-2-(2',3'-dicarboxylcyclopropyl)glycine), and LY354740 (1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicaroxylate monohydrate). In striatal brain slices, LY354740 inhibited evoked excitatory postsynaptic potentials (EPSPs) equally well following either a low- (0.06 Hz) or high (4 Hz)-frequency stimulation of corticostriatal afferents. In contrast, the mGlu2 potentiator cyPPTS (2,2,2-trifluoro-N-[3-(cyclopentyloxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide) inhibited striatal EPSPs only at higher frequencies of stimulation (2 and 4 Hz). Several sulfonamides including 4-MPPTS, 4-APPES (N-[4-(4-carboxamidophenoxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride monohydrate) and/or CBiPES N-[4'-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride) were tested in mGlu2/3 agonist-sensitive rodent model(s) of anxiety and psychosis. As seen with LY354740, both 4-MPPTS and 4-APPES were efficacious in a rat fear-potentiated startle paradigm. Likewise in mice, CBiPES attenuated a stress-induced hyperthermia and PCP-induced hyperlocomotor activity. Furthermore, CBiPES mediated alteration in PCP-induced hyperlocomotor activity was sensitive to mGlu2/3 antagonist pretreatment.


CONCLUSIONS
Taken together, the data indicate mGlu2 receptor potentiators have a unique use-dependent effect on presynaptic glutamate release, and show efficacy in several mGlu2/3-sensitive animal models of psychiatric disorders.
Johnson
Michael P
MP
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, IN 46285, USA. johnson_michael_p@lilly.com
Barda
David
D
Britton
Thomas C
TC
Emkey
Renee
R
Hornback
William J
WJ
Jagdmann
G Erik
GE
McKinzie
David L
DL
Nisenbaum
Eric S
ES
Tizzano
Joseph P
JP
Schoepp
Darryle D
DD
D000818:Animals; D001007:Anxiety / Q000188:drug therapy*; D003521:Cyclopropanes / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine / Q000494:pharmacology; D011618:Psychotic Disorders / Q000188:drug therapy*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects*
D003521:Cyclopropanes; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D010622:Phencyclidine; D005998:Glycine
J Pharmacol Exp Ther. 1999 Oct;291(1):161-70
10490900
Mol Pharmacol. 2001 Nov;60(5):963-71
11641424
Clin Neuropharmacol. 1995 Jun;18(3):237-49
8635182
Naunyn Schmiedebergs Arch Pharmacol. 2000 Jan;361(1):39-46
10651145
Curr Opin Pharmacol. 2002 Feb;2(1):43-9
11786307
J Neurophysiol. 1995 Mar;73(3):1076-83
7608756
Brain. 2002 Dec;125(Pt 12):2635-45
12429591
J Med Chem. 1997 Feb 14;40(4):528-37
9046344
Neuropharmacology. 1999 Dec;38(12 ):1831-9
10608278
J Pharmacol Exp Ther. 2002 Dec;303(3):919-27
12438510
Farmaco. 2002 Dec;57(12):989-92
12564473
Mol Pharmacol. 2003 Sep;64(3):731-40
12920211
Psychopharmacology (Berl). 2000 Mar;148(4):423-9
10928316
Trends Pharmacol Sci. 2002 Jun;23(6):268-74
12084632
Neurosci Lett. 2001 Dec 28;316(3):178-82
11744231
Eur J Pharmacol. 2000 May 26;397(1):R1-2
10844118
Mol Pharmacol. 2003 Oct;64(4):798-810
14500736
Ann N Y Acad Sci. 2003 Nov;1003:481-4
14684495
Neuroscience. 1996 Apr;71(4):949-76
8684625
Neuroreport. 1999 Dec 16;10(18):3923-5
10716234
Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13668-73
14593202
Ann N Y Acad Sci. 2000 Sep;914:284-91
11085328
Brain Res. 2000 Dec 29;887(2):378-84
11134627
Pharmacol Biochem Behav. 2002 Sep;73(2):339-46
12117588
J Psychopharmacol. 2001 Jun;15(2):76-82
11448091
Biochem Pharmacol. 1973 Dec 1;22(23):3099-108
4202581
J Med Chem. 2003 Jul 17;46(15):3189-92
12852748
Psychopharmacology (Berl). 1989;98(2):207-11
2502791
Neuropharmacology. 2000 Apr 27;39(7):1139-46
10760357
Neuroscience. 2003;117(3):697-706
12617973
J Med Chem. 1999 Mar 25;42(6):1027-40
10090786
Bioorg Med Chem Lett. 2004 Jun 21;14(12):3099-102
15149652
Neuropharmacology. 2003 Dec;45(7):895-906
14573382
Am J Psychiatry. 1991 Oct;148(10):1301-8
1654746
Eur J Pharmacol. 2000 Jul 21;400(2-3):221-4
10988337
Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):378-83
14691258
Eur J Pharmacol. 2002 Jan 25;435(2-3):161-70
11821022
Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13402-7
11606768
Br J Pharmacol. 2003 Mar;138(6):1026-30
12684257
Pharmacol Biochem Behav. 2002 Sep;73(2):333-7
12117587
Amino Acids. 2002;23 (1-3):207-11
12373539
Psychopharmacology (Berl). 2003 Aug;168(4):446-54
12709777
Pharmacol Rev. 2002 Jun;54(2):323-74
12037145
Br J Pharmacol. 1998 Feb;123(3):497-504
9504391
J Neurochem. 2004 Jan;88(1):194-202
14675163
J Pharmacol Exp Ther. 1998 Feb;284(2):651-60
9454811
Neuropharmacology. 2001 Jun;40(7):847-55
11378155
Pharmacol Biochem Behav. 2002 Mar;71(3):379-92
11830172
J Neurochem. 2000 Sep;75(3):1147-54
10936197
Pharmacol Biochem Behav. 2002 Sep;73(2):367-74
12117591
Brain Res. 1990 Dec 24;537(1-2):333-6
2085783
Stress. 2003 Sep;6(3):189-97
13129812