3192 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15
Letters
(10) Levine, L.; Gaydos, B.; Sheehan, D.; Goddard, A. W.; Feighner,
J .; Potter, W. Z.; Schoepp, D. D. The mGlu2/3 receptor agonist,
LY354740, reduces panic anxiety induced by a CO2 challenge
in patients diagnosed with panic disorder. Neuropharmacology
2002, 43, 294.
(11) Tizzano, J . P.; Griffey, K.; Schoepp, D. D. The anxiolytic action
of mGlu2/3 receptor agonist, LY354740, in the fear-potentiated
startle model in rats is mechanistically distinct from diazepam.
Pharmacol., Biochem. Behav. 2002, 73, 367-374.
able to completely prevent the effect of the mGlu2
potentiator 3 (Figure 4B) but does not alter the response
seen with diazepam.11 Taken together with the in vitro
characterization of 3, the results indicate that this
pyridylmethylsulfonamide acts in rats to potentiate a
glutamate-mediated stimulation of the mGlu2 receptor
following peripheral dosing.
(12) Helton, D. R.; Tizzano, J . P.; Monn, J . A.; Schoepp, D. D.;
Kallman, M. J . Anxiolytic and side-effect profile of LY354740:
a potent, highly selective, orally active agonist for group II
metabotropic glutamate receptors. J . Pharmacol. Exp. Ther.
1998, 284, 651-660.
(13) Baez, M.; Yang, P.; Kandasamy, R.; Large, T.; Kelly, G.;
Christensen, K.; J ohnson, M. P. Molecular mapping of a subtype
selective site for positive allosteric modulation of the mGlu2
receptor. Neuropharmacology 2002, 43, 274-275.
(14) Britton, T.; Barda, D.; Hornback, W.; J agdmann, G. E.; Henry,
S.; Fichnter, M.; Wang, Z.-Q.; Coleman, D.; Chenoweth, D.;
Vaught, G.; Fivush, A.; Dressman, B.; White, R.; Milot, G.; Herr,
R. J .; Burry, L.; J ohnson, M. P.; Large, T.; Monn, J .; Schoepp,
D. Selective, non-amino acid allosteric potentiators of mGlu2
receptors. Neuropharmacology 2002, 43, 279.
(15) J ohnson, K.; Dieckman, D.; Britton, T.; J ohnson, M.; J agdmann,
E.; Monn, J .; Barda, D.; Henry, S.; Chenoweth, D.; Coleman,
D.; Schoepp, D. Selective, non-amino acid allosteric mGlu2
receptor potentiators inhibit dural plasma protein extravasation;
a potential role in the treatment of migraine. Neuropharmacol-
ogy 2002, 43, 291.
To summarize, the pyridylmethylsulfonamides 2 and
3 are the first reported examples of positive allosteric
modulators of the mGlu2 receptor. These compounds are
selective for the mGlu2 receptor over the other known
mGlu receptors and are unique in that they potentiate
without mimicking the effects of orthosteric agonists.
Like the previously described mGlu1 and GABAb posi-
tive allosteric modulators,24,25 the sulfonamide potentia-
tors binding domain appears to be separate and distinct
from the orthosteric binding site, yet these potentiators
increased the potency of agonists such as glutamate in
functional assays. Thus, 2 and 3 represent a novel class
of allosteric modulators that selectively potentiate the
mGlu2 receptor.
Su p p or tin g In for m a tion Ava ila ble: Synthetic methods
and physicochemical properties of final products and inter-
mediates shown in Scheme 1 and a more detailed description
of the calcium assay methods and conditions utilized in binding
selectivity assays. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) J ohnson, M.; Baez, M.; Britton, T.; J agdmann, G. E., J r.;
J ohnson, K.; J ohnson, B.; Hornback, W.; Large, T.; Nisenbaum,
E.; Tizzano, J .; Monn, J .; Schoepp, D. Subtype-selective positive
allosteric modulators of the metabotropic glutamate 2 receptor:
In vitro and in vivo characterization of novel mGlu2 potentiators.
Neuropharmacology 2002, 43, 291.
(17) Schaffhauser, H.; Rowe, B. A.; Morales, S.; Yin, R.; Chavez-
Noriega, L. E.; Gu, G.; Daggett, L.; Vernier, J . M.; Pinkerton,
T.; Bristow, L. J .; Varney, M. A. In vitro characterization of
N-(′4′-(2-methoxyphenoxy)-phenyl-N-(2,2,2-triflouroethylsulfonyl)-
pyrid-3-ylmethylamine (LY487379) a selective mGlu2 receptor
positive modulator. Neuropharmacology 2002, 43, 307.
(18) Yin, R.; Pinkerton, A.; Vernier, J . M.; Cohen, C.; Bristow, L.;
Chavez-Noriega, L. E. Modulation of medial perforant path-
dentate granule cell synapses by the mGluR2 potentiator N-(′4′-
(2-methoxyphenoxy)-phenyl-N-(2,2,2-triflouroethylsulfonyl)-pyrid-
3-ylmethylamine (LY487379). Neuropharmacology 2002, 43, 313.
(19) Desai, M. A.; Burnett, J . P.; Mayne, N. G.; Schoepp, D. D.
Pharmacological characterization of desensitization in a human
mGlu1 alpha-expressing non-neuronal cell line co-transfected
with a glutamate transporter. Br. J . Pharmacol. 1996, 118,
1558-1564.
(20) Desai, M. A.; Burnett, J . P.; Mayne, N. G.; Schoepp, D. D. Cloning
and expression of a human metabotropic glutamate receptor 1
alpha: enhanced coupling on co-transfection with a glutamate
transporter. Mol. Pharmacol. 1995, 48, 648-657.
(21) Wu, S.; Wright, R. A.; Rockey, P. K.; Burgett, S. G.; Arnold, J .
S.; Rosteck, P. R., J r.; J ohnson, B. G.; Schoepp, D. D.; Belagaje,
R. M. Group III human metabotropic glutamate receptors 4, 7
and 8: molecular cloning, functional expression, and comparison
of pharmacological properties in RGT cells. Mol. Brain Res. 1998,
53, 88-97.
(22) Offermanns, S.; Simon, M. I. GR15 and GR16 couple a wide
variety of receptors to phospholipase C. J . Biol. Chem. 1995,
270, 15175-15180.
(23) Gomeza, J .; Mary, S.; Brabet, I.; Parmentier, M. L.; Restituito,
S.; Bockaert, J .; Pin, J . P. Coupling of metabotropic glutamate
receptors 2 and 4 to GR15, GR16, and chimeric GRq/i proteins:
characterization of new antagonists. Mol. Pharmacol. 1996, 50,
923-930.
(24) Urwyler, S.; Mosbacher, M.; Lingenhoehl, K.; Heid, J .; Froestl,
W.; Bettler, B.; Kaupmann, K. Positive allosteric modulation of
native and recombinant γ-aminobutyric acidB receptors by 2,6-
di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930)
and its aldehyde analog CGP13501. Mol. Pharmacol. 2001, 60,
963-971.
(25) Knoflach, F.; Mutel, V.; J olidon, S.; Kew, J . N. C.; Malherbe, P.;
Vieira, E.; Wichmann, J .; Kemp, J . A. Positive allosteric modula-
tors of metabotropic glutamate 1 receptor: Characterization,
mechanism of action, and binding site. Proc. Natl. Acad. Sci.
U.S.A. 2001, 98, 13402-13407.
Refer en ces
(1) Schoepp, D. D.; J ane, D. E.; Monn, J . A. Pharmacological agents
acting at subtypes of metabotropic glutamate receptors. Neu-
ropharmacology 1999, 38, 1431-1476.
(2) Cartmell, J .; Schoepp, D. D. Regulation of neurotransmitter
release by metabotropic glutamate receptors. J . Neurochem.
2000, 75, 889-907.
(3) Monn, J . A.; Valli, M. J .; Massey, S. M.; Wright, R. A.; Salhoff,
C. R.; J ohnson, B. G.; Howe, T.; Alt, C. A.; Rhodes, G. A.; Robey,
R. L.; Griffey, K. R.; Tizzano, J . P.; Kallman, M. J .; Helton, D.
R.; Schoepp, D. D. Design, synthesis, and pharmacological
characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicar-
boxylic acid (LY354740): a potent, selective, and orally active
group 2 metabotropic glutamate receptor agonist possessing
anticonvulsant and anxiolytic properties. J . Med. Chem. 1997,
40, 528-537.
(4) Monn, J . A.; Valli, M. J .; Massey, S. M.; Hansen, M. M.; Kress,
T. J .; Wepsiec, J . P.; Harkness, A. R.; Grutsch, J . L., J r.; Wright,
R. A.; J ohnson, B. G.; Andis, S. L.; Kingston, A.; Tomlinson, R.;
Lewis, R.; Griffey, K. R.; Tizzano, J . P.; Schoepp, D. D. Synthesis,
pharmacological characterization, and molecular modeling of
heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0]-
hexane-2,6-dicarboxylic acid (LY354740): identification of two
new potent, selective, and systemically active agonists for group
II metabotropic glutamate receptors. J . Med. Chem. 1999, 42,
1027-1040.
(5) Lam, A. G.; Soriano, M. A.; Monn, J . A.; Schoepp, D. D.; Lodge,
D.; McCulloch, J . Effects of the selective metabotropic glutamate
agonist LY354740 in
Neurosci. Lett. 1998, 254, 121-123.
a rat model of permanent ischaemia.
(6) Kingston, A. E.; O’Neill, M. J .; Lam, A.; Bales, K. R.; Monn, J .
A.; Schoepp, D. D. Neuroprotection by metabotropic glutamate
receptor glutamate receptor agonists: LY354740, LY379268 and
LY389795. Eur. J . Pharmacol. 1999, 377, 155-165.
(7) Marek, G. J .; Wright, R. A.; Schoepp, D. D.; Monn, J . A.;
Aghajanian, G. K. Physiological antagonism between 5-hydroxy-
tryptamine(2A) and group II metabotropic glutamate receptors
in prefrontal cortex. J . Pharmacol. Exp. Ther. 2000, 292, 76-
87.
(8) Cartmell, J .; Monn, J . A.; Schoepp, D. D. The metabotropic
glutamate 2/3 receptor agonists LY354740 and LY379268 se-
lectively attenuate phencyclidine versus d-amphetamine motor
behaviors in rats. J . Pharmacol. Exp. Ther. 1999, 291, 161-
170.
(9) Battaglia, G.; Monn, J . A.; Schoepp, D. D. In vivo inhibition of
veratridine-evoked release of striatal excitatory amino acids by
the group II metabotropic glutamate receptor agonist LY354740
in rats. Neurosci. Lett. 1997, 229, 161-164.
J M034015U