In vitro pharmacological and rat pharmacokinetic characterization of LY3020371, a potent and selective mGlu 2/3 receptor antagonist

Witkin, Jeffrey M.; Ornstein, Paul L.; Mitch, Charles H.; Li, Renhua; Smith, Stephon C.; Heinz, Beverly A.; Wang, Xu Shan; Xiang, Chuanxi; Carter, Joan H.; Anderson, Wesley; Li, Xia; Broad, Lisa M.; Pasqui, Francesca; Fitzjohn, Stephen M.; Sanger, Helen; Smith, Jodi L.; Catlow, John T.; Swanson, Steven; Monn, James A.

doi:10.1016/j.neuropharm.2015.12.021

Cited by 22 publications

(15 citation statements)

References 91 publications

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“…This limitation has been overcome with LY3027788.HCl, a diester form of LY3020371 (Smith et al, 2012) that demonstrates rapid absorption and bioconversion to LY3020371 following oral dosing in rodents. Oral doses at or above 10 mg/kg LY3027788.HCl in rats generated CSF levels of LY3020371 that either reached or exceeded the measured antagonist potency for this compound in the rat hippocampal slice (IC 50 5 46 nM) (Witkin et al, 2016b) and doses at or above 10 mg/kg enhanced wakefulness in rats. Similarly, in mice, functional mGlu2/3 antagonist-associated brain levels of LY3020371 (i.e., concentrations at or above 46 nM) measured 1 hour after single oral doses of LY3027788.…”

Section: Discussionmentioning

confidence: 95%

“…A new orthosteric antagonist of mGlu2/3 receptors, LY3020371, was recently reported (Smith et al, 2012) and characterized as a potent and selective orthosteric antagonist in vitro (Witkin et al, 2016b). The pharmacology of LY3020371 from human clonal systems to native tissue functional preparations along with its pharmacokinetic properties suggested that LY3020371 was a well-behaved orthosteric mGlu2/3 receptor antagonist that would block mGlu2/3 receptors in vivo upon systemic dosing (Witkin et al, 2016b). In the present paper we documented the in vivo effects of LY3020371and its diester prodrug, LY3027788 (Smith et al, 2012) that predict efficacy in treatment-resistant depression.…”

Section: Discussionmentioning

confidence: 99%

“…These results are similar to previously disclosed findings for rat CSF/plasma pharmacokinetics following i.v. dosing of LY3020371 (Witkin et al, 2016b) as well as to those associated with mGlu2/3 receptor agonists possessing similar physiochemical characteristics (Monn et al, 2015a,b).…”

Section: Antidepressant-like Effects In Serotonin Uptake Inhibitor-sementioning

confidence: 99%

“…This molecule was characterized as a highly potent and selective orthosteric antagonist of recombinant human mGlu2/3 receptors, endogenously expressed rat cortical and hippocampal mGlu2/3 receptors, and native mGlu2/3 receptors present in synaptosomes prepared from surgically resected human brain tissue (Witkin et al, 2016b). We further demonstrated that when administered by the intravenous route at doses between 0.3 and 10 mg/kg, exposures of LY3020371 in the cerebrospinal fluid (CSF) fully covered concentrations required to effectively block mGlu2/3 receptor activation in native tissues (Witkin et al, 2016b). Based on these data, LY3020371 was considered an exemplary tool with which to probe the biologic significance of mGlu2/3 receptor antagonism in vivo by parenteral dosing.…”

Section: Introductionmentioning

confidence: 99%

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Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.

Witkin

Mitchell

Wafford

et al. 2017

J Pharmacol Exp Ther

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The ability of the -methyl-d-aspartate receptor antagonist ketamine to alleviate symptoms in patients suffering from treatment-resistant depression (TRD) is well documented. In this paper, we directly compare in vivo biologic responses in rodents elicited by a recently discovered metabotropic glutamate (mGlu) 2/3 receptor antagonist 2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY3020371) with those produced by ketamine. Both LY3020371 and ketamine increased the number of spontaneously active dopamine cells in the ventral tegmental area of anesthetized rats, increased O in the anterior cingulate cortex, promoted wakefulness, enhanced the efflux of biogenic amines in the prefrontal cortex, and produced antidepressant-related behavioral effects in rodent models. The ability of LY3020371 to produce antidepressant-like effects in the forced-swim assay in rats was associated with cerebrospinal fluid (CSF) drug levels that matched concentrations required for functional antagonist activity in native rat brain tissue preparations. Metabolomic pathway analyses from analytes recovered from rat CSF and hippocampus demonstrated that both LY3020371 and ketamine activated common pathways involving GRIA2 and ADORA1. A diester analog of LY3020371 [bis(((isopropoxycarbonyl)oxy)-methyl) (1,2,3,4,5,6)-2-amino-3-(((3,4-difluorophenyl)thio)methyl)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (LY3027788)] was an effective oral prodrug; when given orally, it recapitulated effects of intravenous doses of LY3020371 in the forced-swim and wake-promotion assays, and augmented the antidepressant-like effects of fluoxetine or citalopram without altering plasma or brain levels of these compounds. The broad overlap of biologic responses produced by LY3020371 and ketamine supports the hypothesis that mGlu2/3 receptor blockade might be a novel therapeutic approach for the treatment of TRD patients. LY3020371 and LY3027788 represent molecules that are ready for clinical tests of this hypothesis.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Antidepressant-like Effects In Serotonin Uptake Inhibitor-sementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.

Witkin

Mitchell

Wafford

et al. 2017

J Pharmacol Exp Ther

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“…Novel mGlu2/3 receptor antagonists with properties conducive to i.v. testing of this hypothesis in patients have recently been characterized (Witkin et al, 2016) and await clinical proof of concept studies.…”

Section: Discussionmentioning

confidence: 99%

The Rapidly Acting Antidepressant Ketamine and the mGlu2/3 Receptor Antagonist LY341495 Rapidly Engage Dopaminergic Mood Circuits

Witkin

Monn

Schoepp

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Ketamine is a rapidly acting antidepressant in patients with treatment-resistant depression (TRD). Although the mechanisms underlying these effects are not fully established, inquiry to date has focused on the triggering of synaptogenesis transduction pathways via glutamatergic mechanisms. Preclinical data suggest that blockade of metabotropic glutamate (mGlu2/3) receptors shares many overlapping features and mechanisms with ketamine and may also provide rapid efficacy for TRD patients. Central dopamine circuitry is recognized as an end target for mood regulation and hedonic valuation and yet has been largely neglected in mechanistic studies of antidepressant-relevant effects of ketamine. Herein, we evaluated the changes in dopaminergic neurotransmission after acute administration of ketamine and the mGlu2/3 receptor antagonist LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid ] in preclinical models using electrophysiologic, neurochemical, and behavioral endpoints. When given acutely, both ketamine and LY341495, but not the selective serotonin reuptake inhibitor (SSRI) citalopram, increased the number of spontaneously active dopamine neurons in the ventral tegmental area (VTA), increased extracellular levels of dopamine in the nucleus accumbens and prefrontal cortex, and enhanced the locomotor stimulatory effects of the dopamine D 2/3 receptor agonist quinpirole. Further, both ketamine and LY341495 reduced immobility time in the tail-suspension assay in CD1 mice, which are relatively resistant to SSRI antidepressants. Both the VTA neuronal activation and the antidepressant phenotype induced by ketamine and LY341495 were attenuated by the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-(9CI)-benzo[f]quinoxaline-7-sulfonamide, indicating AMPA-dependent effects. These findings provide another overlapping mechanism of action of ketamine and mGlu2/3 receptor antagonism that differentiates them from conventional antidepressants and thus support the potential rapidly acting antidepressant actions of mGlu2/3 receptor antagonism in patients.

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mGlu2/3 receptor antagonists for depression: overview of underlying mechanisms and clinical development

Chaki

Watanabe²

2023

Eur Arch Psychiatry Clin Neurosci

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In vitro pharmacological and rat pharmacokinetic characterization of LY3020371, a potent and selective mGlu 2/3 receptor antagonist

Cited by 22 publications

References 91 publications

Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.

Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.

The Rapidly Acting Antidepressant Ketamine and the mGlu2/3 Receptor Antagonist LY341495 Rapidly Engage Dopaminergic Mood Circuits

mGlu2/3 receptor antagonists for depression: overview of underlying mechanisms and clinical development

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