生物活性

• 描述Metabotropic glutamate (mGlu) receptors are Class C 7-transmembrane domain (7-TMD) G-protein coupled receptors (GPCRs) involved in the modulation of neurotransmission throughout the nervous system ^[3]. LY2979165 is the alanine prodrug of 2812223, a selective orthosteric mGluR2 agonist. It has been developed with the aim of normalizing aberrant glutamatergic activity in the human brain, and dose-dependently reversed ketamine-evoked increases in glucose metabolism in the rat brain as assayed by 2-deoxyglucose (2-DG) autoradiography ^[4]. LY2979165 would attenuate the ketamine-evoked BOLD (blood oxygenation level dependent) signal in a dose- and exposure-dependent fashion. A significant mean decrease of 45% in the ketamine-evoked signal at the 60-mg dose of LY2979165 compared to placebo, while the 20-mg dose showed an intermediate level of effect but no statistical separation from placebo. Additionally, pretreatment with LY2979165 dose-dependently augmented the ketamine-induced increases in the cognitive and positive subscales (PANSS), statistically significant (P = 0.008 and P = 0.005, respectively) at the 60-mg dose compared to placebo) ^[4].
• 作用机制LY2979165 is a mGlu2 agonist, a drug candidate drug used to treat bipolar disorder.
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01248052	Bipolar Disorder	Phase 1	Completed	-	Singapore ... more >> For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern time (UTC/GMT - 5 hours, EST), or speak with your personal physician Singapore, Singapore Collapse <<
  NCT03044249	Psychosis Dem... more >>entia Aggression Agitation Alzheimer Dementia Collapse <<	Phase 2	Recruiting	January 2021	United States, Connecticut ... more >> Associated Neurologists of Southern CT Recruiting Fairfield, Connecticut, United States, 06824 Contact: Srinath Kadimi    203-333-1151    skadimi@anscneuro.com    Principal Investigator: Srinath Kadimi          United States, Florida Marcus Neuroscience Institute Recruiting Boca Raton, Florida, United States, 33486 Contact: Jonathan Harris          Contact: Margaret Scott    561-955-5784    MScott@brrh.com    Principal Investigator: Jonathan Harris          Meridien Research Recruiting Brooksville, Florida, United States, 34601 Contact: James Andersen    352-597-8839    jandersen@meridienresearch.net    Principal Investigator: James Andersen          Galiz Research Recruiting Hialeah, Florida, United States, 33016 Contact: Jose Gamez    305-805-0921    jegamez@galizresearch.com    Principal Investigator: Jose Gamez          Galiz Research Recruiting Miami Springs, Florida, United States, 33166 Contact: Jose Gamez    305-820-3381    jegamez@galizresearch.com    Principal Investigator: Jose Gamez          Parkinson's Disease Treatment Center of SW Florida Recruiting Port Charlotte, Florida, United States, 33980 Contact: Ramon Gil    941-743-4987    dawnm@ParkinsonsFL.com    Principal Investigator: Ramon Gil, MD          Meridien Research Inc Recruiting Saint Petersburg, Florida, United States, 33709 Contact: Gigi Lefebvre    727-347-8839    glefebvre@meridienresearch.net    Principal Investigator: Gigi Lefebvre          University of South Florida Recruiting Tampa, Florida, United States, 33613 Contact: Jean Fils    813-974-9958    jfils@health.usf.edu    Principal Investigator: Jean Fils          United States, Kansas College Park Family Care Neuro Recruiting Overland Park, Kansas, United States, 66212 Contact: Jeffrey Kaplan    913-438-0868    jeffrey.kaplan@hcahealthcare.com    Principal Investigator: Jeffrey Kaplan          United States, Louisiana J. Gary Booker, MD, Clinical Trials Recruiting Shreveport, Louisiana, United States, 71104 Contact: J G Booker    318-227-9600    drjgarybooker@bellsouth.net    Principal Investigator: J G Booker, MD          United States, New Jersey Alzheimer's Research Corporation Suspended Manchester, New Jersey, United States, 08759 United States, New York Richmond Behavioral Associates Recruiting Staten Island, New York, United States, 10312 Contact: Mark DiBuono    718-317-5522 ext 3    dibuono@rbany.com    Principal Investigator: Mark DiBuono          United States, Ohio Neurology Diagnostics Inc Recruiting Dayton, Ohio, United States, 45459 Contact: Joel Vandersluis    937-224-8200    drv.clinicaltrials@ndidayton.com    Principal Investigator: Joel Vandersluis          Canada, Ontario SKDS Research Inc. Recruiting Newmarket, Ontario, Canada, L3Y 5G8 Contact: Sam Henein    905-898-7582    research@skds.ca    Principal Investigator: Sam Henein, MD          Canada, Quebec Montreal Neurological Institute Recruiting Montréal, Quebec, Canada, H3A 2B4 Contact: Simon Ducharme    514-398-1911    simon.ducharme@mcgill.ca    Principal Investigator: Simon Ducharme Collapse <<
  NCT01383967	Bipolar Disorder	Phase 1	Completed	-	Singapore ... more >> For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Singapore, Singapore Collapse <<

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• 参考文献

• [1] Hanna L, Ceolin L, et al. Differentiating the roles of mGlu2 and mGlu3 receptors using LY541850, an mGlu2 agonist/mGlu3 antagonist. Neuropharmacology. 2013 Mar;66:114-21.

  [2] Ceolin L, Kantamneni S, et al. Study of novel selective mGlu2 agonist in the temporo-ammonic input to CA1 neurons reveals reduced mGlu2 receptor expression in a Wistar substrain with an anxiety-like phenotype. J Neurosci. 2011 May 4;31(18):6721-31.

  [3] O'Brien DE, Conn PJ. Neurobiological Insights from mGlu Receptor Allosteric Modulation. Int J Neuropsychopharmacol. 2016 Apr 29;19(5):pyv133. doi: 10.1093/ijnp/pyv133. PMID: 26647381; PMCID: PMC4886670.

  [4] Mehta MA, Schmechtig A, Kotoula V, McColm J, Jackson K, Brittain C, Tauscher-Wisniewski S, Kinon BJ, Morrison PD, Pollak T, Mant T, Williams SCR, Schwarz AJ. Group II metabotropic glutamate receptor agonist prodrugs LY2979165 and LY2140023 attenuate the functional imaging response to ketamine in healthy subjects. Psychopharmacology (Berl). 2018 Jul;235(7):1875-1886. doi: 10.1007/s00213-018-4877-9. Epub 2018 Mar 21. PMID: 29564482.