hmGluR2 (EC50 = 2.69 nM); hmGluR3 (EC50 = 4.48 nM); hmGluR2 (Ki = 14.1 nM); hmGluR3 (Ki = 5.8 nM)
LY379268 targets group II metabotropic glutamate receptors, specifically mGluR2 and mGluR3. It acts as a highly selective agonist with EC50 values of 2.69 nM (mGluR2) and 4.48 nM (mGluR3), displaying >80-fold selectivity over group I and group III receptors.

After subjecting astrocytes to LY379268 (0.1 μM; 24-48 hours) for nine weeks (9w), there was a decrease in mitochondrial ROS levels and apoptosis and an increase in mGlu3R and Nrf2 protein levels and SOD activity. In co-culture studies, mGlu3R activation in aging astrocytes also inhibited Aβ1-42-induced hippocampus neuronal loss. Antioxidant effects and protection of hippocampal neurons from Aβ-induced neurotoxicity are shown when mGlu3R is activated in aged astrocytes [3].

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LY379268 potently activates mGluR2 and mGluR3 with low nanomolar EC50 values. It demonstrates high selectivity for group II receptors over other mGluR subtypes. The compound has been used to study the physiological and pathological roles of group II mGluRs in the central nervous system.

In the case of LY379268, the start of inflammatory hyperalgesia was greatly delayed without impacting paw inflammation when a dose of 3 mg/kg was administered prior to plantar injection of carrageenan [2]. Before subcutaneously injecting capsaicin into the tail of a mouse used in a tail-retraction experiment with warm water, LY379268 (12 mg/kg; i.p.) was administered to minimize the ensuing neurogenic hyperalgesia [2].

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1. Previous studies investigating the role of metabotropic glutamate (mGlu) receptors in nociceptive processing have been hampered by the lack of systemically active, selective, ligands. This study investigates the possible analgesic and/or anti-hyperalgesic properties of the most potent compound to date that has systemic agonist activity at group II mGlu receptors, LY379268. 2. In testing the drug in rats as an analgesic to acute noxious stimuli, LY379268 (in doses up to 3 mg kg(-1) i.p.) did not affect withdrawal latencies to either mechanical or thermal stimulation. 3. However, when a 3 mg kg(-1) dose was given prior to an intraplantar injection of carrageenan, the inflammatory hyperalgesia that developed was significantly delayed compared to saline pre-treated controls, without affecting the inflammation of the paw. A similar dose of the mGlu-inactive enantiomer, LY379267, was not anti-hyperalgesic. 4. In a model of mouse tail withdrawal to warm water, LY379268 (12 mg kg(-1) i.p.), given before a subcutaneous tail injection of capsaicin, reduced the subsequent neurogenic hyperalgesia. 5. Rota-rod testing showed that the drug did not produce a motor impairment in rats at antihyperalgesic doses. 6. The results indicate that systemic activation of this group of mGlu receptors reduces both inflammatory and neurogenic thermal hyperalgesia [2].

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In vivo, LY379268 has demonstrated neuroprotective effects. It reduces methamphetamine self-administration in rats and attenuates ketamine-induced behavioral and neurochemical changes. The compound shows potential for the treatment of neuropsychiatric disorders.

As part of our ongoing research program aimed at the identification of highly potent, selective, and systemically active agonists for group II metabotropic glutamate (mGlu) receptors, we have prepared novel heterobicyclic amino acids (-)-2-oxa-4-aminobicyclo[3.1. 0]hexane-4,6-dicarboxylate (LY379268, (-)-9) and (-)-2-thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-10). Compounds (-)-9 and (-)-10 are structurally related to our previously described nanomolar potency group II mGlu receptor agonist, (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740 monohydrate, 5), with the C4-methylene unit of 5 being replaced with either an oxygen atom (as in (-)-9) or a sulfur atom (as in (-)-10). Compounds (-)-9 and (-)-10 potently and stereospecifically displaced specific binding of the mGlu2/3 receptor antagonist ([3H]LY341495) in rat cerebral cortical homogenates, displaying IC50 values of 15 +/- 4 and 8.4 +/- 0.8 nM, respectively, while having no effect up to 100 000 nM on radioligand binding to the glutamate recognition site on NMDA, AMPA, or kainate receptors. Compounds (-)-9 and (-)-10 also potently displaced [3H]LY341495 binding from membranes expressing recombinant human group II mGlu receptor subtypes: (-)-9, Ki = 14.1 +/- 1.4 nM at mGlu2 and 5.8 +/- 0.64 nM at mGlu3; (-)-10, Ki = 40.6 +/- 3.7 nM at mGlu2 and 4.7 +/- 1.2 nM at mGlu3. Evaluation of the functional effects of (-)-9 and (-)-10 on second-messenger responses in nonneuronal cells expressing human mGlu receptor subtypes demonstrated each to be a highly potent agonist for group II mGlu receptors: (-)-9, EC50 = 2.69 +/- 0.26 nM at mGlu2 and 4.58 +/- 0.04 nM at mGlu3; (-)-10, EC50 = 3.91 +/- 0.81 nM at mGlu2 and 7.63 +/- 2. 08 nM at mGlu3. In contrast, neither compound (up to 10 000 nM) displayed either agonist or antagonist activity in cells expressing recombinant human mGlu1a, mGlu5a, mGlu4a, or mGlu7a receptors. The agonist effects of (-)-9 and (-)-10 at group II mGlu receptors were not totally specific, however, as mGlu6 agonist activity was observed at high nanomolar concentrations for (-)-9 (EC50 = 401 +/- 46 nM) and at micromolar concentrations (EC50 = 2 430 +/- 600 nM) for (-)-10; furthermore, each activated mGlu8 receptors at micromolar concentrations (EC50 = 1 690 +/- 130 and 7 340 +/- 2 720 nM, respectively). Intraperitoneal administration of either (-)-9 or (-)-10 in the mouse resulted in a dose-related blockade of limbic seizure activity produced by the nonselective group I/group II mGluR agonist (1S,3R)-ACPD ((-)-9 ED50 = 19 mg/kg, (-)-10 ED50 = 14 mg/kg), indicating that these molecules effectively cross the blood-brain barrier following systemic administration and suppress group I mGluR-mediated limbic excitation [1].

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In vitro receptor binding assays typically measure the displacement of a radiolabeled group II mGluR ligand from membrane preparations. LY379268 is incubated with membranes expressing mGluR2 or mGluR3, and the IC50 is determined. Functional assays measure receptor activation using GTPγS binding or cAMP inhibition in cells expressing the receptors.

Astrocytes play a key role by providing antioxidant support to nearby neurons under oxidative stress. We have previously demonstrated that in vitro astroglial subtype 3 metabotropic glutamate receptor (mGlu3R) is neuroprotective. However, its role during aging has been poorly explored. Our study aimed to determine whether LY379268, an mGlu3R agonist, exerts an antioxidant effect on aged cultured rat astrocytes. Aged cultured astrocytes obtained after 9-weeks (9w) in vitro were positive for β-galactosidase stain, showed decreased mGlu3R and glutathione (GSH) levels and superoxide dismutase (SOD) activity, while nuclear erythroid factor 2 (Nrf2) protein levels, reactive oxygen species (ROS) production and apoptosis were increased. Treatment of 9w astrocytes with LY379268 resulted in an increase in mGlu3R and Nrf2 protein levels and SOD activity, and decreased mitochondrial ROS levels and apoptosis. mGlu3R activation in aged astrocytes also prevented hippocampal neuronal death induced by Aβ1-42 in co-culture assays. We conclude that activation of mGlu3R in aged astrocytes had an anti-oxidant effect and protected hippocampal neurons against Aβ-induced neurotoxicity. The present study suggests mGlu3R activation in aging astrocytes as a therapeutic strategy to slow down age-associated neurodegeneration [3].

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In vitro cellular assays evaluate the agonist activity of LY379268 on cells expressing mGluR2 or mGluR3. Cells are treated with LY379268, and receptor activation is measured by inhibition of forskolin-stimulated cAMP accumulation. The EC50 for receptor activation is determined from dose-response curves. Selectivity over other mGluR subtypes is confirmed using cells expressing group I and III receptors.

LY379268 and its mGlu receptor-inactive enantiomer, LY379267 were dissolved in equimolar NaOH and adjusted to a pH of 7 – 9 with equimolar HCl. [2]

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Experimental design [2]
The experimenter was ‘blind' to the treatment under test. In all tests, ‘control' readings were taken immediately before i.p. injection of either vehicle (saline) or test agent (LY379268 or LY379267) in a volume of 2 ml kg−1, and before the induction of hyperalgesia.

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Protocol 1 [2]
The analgesic effects of LY379268 or LY379267 were tested on responses to thermal and mechanical stimuli (PWL and PWT) in rats without hind paw inflammation.

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Protocol 2 [2]
The analgesic effects of LY379268 were tested in mice on TWL to hot water at 50°C. To match protocol 6 below, tests were repeated four times at 3 min intervals 1 h after drug administration.

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Protocol 3 [2]
The ability of LY379268 to reverse inflammatory hyperalgesia was tested by i.p. injection 3 h after carrageenan injection. Thermal PWL was tested hourly for a further 3 h.

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Protocol 4 [2]
The ability of LY379268 to prevent the induction of inflammatory hyperalgesia was assessed by administering drug concurrently with carrageenan, after having made baseline readings of PWL. Measurements of thermal PWL were made hourly for the following 4 h.

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Protocol 5 [2]
As Protocol 4 but drug was administered 1 h before carrageenan was injected into one hind paw. PWLs were then tested hourly for a further 4 h.

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Protocol 6 [2]
LY379268 or vehicle was given 1 h prior to an injection of capsaicin into the tail of mice. The degree of neurogenic thermal hyperalgesia was tested by TWL to warm water at 47°C. This lower water temperature than for Protocol 2 gave baseline latencies close to cut off so as to maximize the ability to detect hyperalgesia. TWL tests were repeated before and 3, 6 and 9 min after capsaicin.

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In vivo animal experiments are conducted in rodent models of neuropsychiatric disorders. LY379268 is administered via intraperitoneal or oral routes. Behavioral tests such as locomotor activity, prepulse inhibition, and drug self-administration are performed. Neurochemical changes are assessed by microdialysis or tissue analysis.

LY379268 has a molecular formula of C7H9NO5 and a molecular weight of 187.15. It is also known as (1R,4R,5S,6R)-4-Amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid. The compound has a purity of ≥98%. It should be stored under recommended conditions as per the certificate of analysis.

The toxicity profile of LY379268 is derived from preclinical studies. As a group II mGluR agonist, its effects are related to modulation of glutamatergic signaling. No significant toxicity has been reported in the available literature at the doses used in research studies.

[1]. 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 Mar 25;42(6):1027-40.

[2]. Systemic pre-treatment with a group II mGlu agonist, LY379268, reduces hyperalgesia in vivo. Br J Pharmacol. 2002 Mar;135(5):1255-62.

[3]. Antioxidant and neuroprotective effects of mGlu3 receptor activation on astrocytes aged in vitro. Neurochem Int. 2020 Nov;140:104837.

LY 379268 is an organic heterobicyclic compound with the structure (1R,5S)-2-oxabicyclo[3.1.0]hexane, with amino, carboxyl, and carboxyl groups attached at positions 4R, 4R, and 6R, respectively. It is a potent agonist of type II metabotropic glutamate receptors mGluR2 and mGluR3 (EC50 values of 2.69 nM and 4.48 nM, respectively), exhibiting antipsychotic-like effects in animal models of schizophrenia. It can be used as a metabotropic glutamate receptor agonist, neuroprotective agent, antipsychotic, and anxiolytic. It is an organic heterobicyclic compound, a bridging compound, and also an aminodicarboxylic acid. LY379268 (−)-9) and LY389795 (−)-10) are the most potent type II metabotropic glutamate receptor agonists reported to date. The high mGlu2/3 receptor potency and selectivity exhibited by these heterobicyclic amino acids further provide experimental evidence to support the hypothesis that glutamate interacts with mGlu2/3 receptors in a fully extended conformation. Similar to compound 5, heterocyclic compounds (−)-9 and (−)-10 effectively penetrated the blood-brain barrier into the central nervous system after systemic administration and blocked type I mGlu receptor activation-induced seizures. Therefore, similar to compound 5, these compounds may be helpful in studying the function of mGlu2/3 receptors in vitro and in vivo. [1] In rats, doses of LY379268, which has an anti-hypnotic effect, had no effect on rotarod test performance (see Simmons et al., 1998). However, studies on higher doses of LY379268 were limited due to the induction of hyper-startle responses. Given that other compounds in this structural series have not shown the same effect (unpublished observations), this effect may reflect its activity against other glutamate receptors (possibly mGlu8, against which LY379268 is active in vitro; Monn et al., 1999) or non-glutamate receptors. LY379267 is the enantiomer of LY379268 and has no agonist or antagonist activity against any mGlu receptor subtype (unpublished data), and no anti-hyperalgesic effect was observed in this study, although it did lead to an unexplained enhancement of carrageenan hyperalgesia without affecting baseline values; this may be due to some unknown non-mGlu receptor interaction. In summary, this study shows that systemic activation of group II mGlu receptors can shorten the induction period of hyperalgesia at this dose without producing motor or other obvious side effects. This provides impetus for further analysis of the relative roles of mGlu2 and mGlu3 receptor subtypes in the central sensitization process associated with persistent pain. [2]

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LY379268 is a research tool used to study the role of group II mGluRs in synaptic transmission, neuronal plasticity, and neuropsychiatric disorders. It has been investigated for its potential in anxiety, schizophrenia, and addiction. The compound is also known as LY 379268.

C7H9NO5

187.15006

187.048

C, 44.92; H, 4.85; N, 7.48; O, 42.74

191471-52-0

10197984

White to off-white solid powder

-4.3

3

6

2

13

291

4

C1[C@]([C@@H]2[C@H]([C@@H]2O1)C(=O)O)(C(=O)O)N

YASVRZWVUGJELU-MDASVERJSA-N

InChI=1S/C7H9NO5/c8-7(6(11)12)1-13-4-2(3(4)7)5(9)10/h2-4H,1,8H2,(H,9,10)(H,11,12)/t2-,3-,4+,7+/m1/s1

(1S,2R,5R,6R)-2-amino-4-oxabicyclo[3.1.0]hexane-2,6-dicarboxylic acid

LY379268; LY 379268; 191471-52-0; (1R,4R,5S,6R)-4-Amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid; LY-379268; 2-Oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid, 4-amino-, (1R,4R,5S,6R)-; CHEMBL275079; S96JF4J697; LY-379268.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

0.1 M NaOH : ~200 mg/mL (~1068.66 mM)
H2O : ~2 mg/mL (~10.69 mM)

Solubility in Formulation 1: 25 mg/mL (133.58 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)