Preclinical Characterization of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate N-Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder.
Linda J Bristow, Jyoti Gulia, Michael R Weed, Bettadapura N Srikumar, Yu-Wen Li, John D Graef, Pattipati S Naidu, Charulatha Sanmathi, Jayant Aher, Tanmaya Bastia, Mahesh Paschapur, Narasimharaju Kalidindi, Kuchibhotla Vijaya Kumar, Thaddeus Molski, Rick Pieschl, Alda Fernandes, Jeffrey M Brown, Digavalli V Sivarao, Kimberly Newberry, Mark Bookbinder, Joseph Polino, Deborah Keavy, Amy Newton, Eric Shields, Jean Simmermacher, James Kempson, Jianqing Li, Huiping Zhang, Arvind Mathur, Raja Reddy Kallem, Meenakshee Sinha, Manjunath Ramarao, Reeba K Vikramadithyan, Srinivasan Thangathirupathy, Jayakumar Warrier, Imadul Islam, Joanne J Bronson, Richard E Olson, John E Macor, Charlie F Albright, Dalton King, Lorin A Thompson, Lawrence R Marcin, Michael Sinz
Journal of Pharmacology and Experimental Therapeutics December 2017 DOI: 10.1124/jpet.117.242784 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical drug discovery and characterization study Peer reviewed |
|---|---|
| Population | Xenopus oocytes expressing human NMDA receptor subtypes, mice, and cynomolgus monkeys |
| Interventions | BMS-986169 BMS-986163 |
| Measures | quantitative electroencephalogram (qEEG) |
| Topics | Depression |
| Key points | BMS-986169 and its prodrug BMS-986163 are selective GluN2B negative allosteric modulators that engage the target and produce ketamine-like antidepressant-relevant effects in rodents without ketamine-like hyperlocomotion, though transient working memory impairment occurred in monkeys. BMS-986163 was selected as the lead intravenous candidate for treatment-resistant depression because of the poor aqueous solubility of BMS-986169. |
Abstract
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate N-methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-d-aspartate receptor subtypes (IC50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC50 = 28.4 μM) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.
Comparable studies
Other preclinical and animal studies on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats | 2020 | Preclinical study | |
| A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Rats with spared nerve injury (neuropathic pain model), sham-operated rats, and control... | 2011 | Animal experimental study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study | |
| A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Mice and cultured rat cortical neurons | 2023 | Preclinical study | |
| Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model Susceptible mice after chronic social defeat stress | 2017 | Preclinical animal study |
Citations in the library
Cited by 2
Cites 6
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- A Randomized, Placebo-Controlled, Crossover Pilot Trial of the Oral Selective NR2B Antagonist MK-0657 in Patients With Treatment-Resistant Major Depressive Disorder Journal of Clinical Psychopharmacology June 20, 2012
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- GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine Elife October 23, 2014
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