Author: Kwan, Cynthia ; Frouni, Imane ; Kang, Woojin ; Huot, Philippe ; Nuara, Stephen G ; Bédard, Dominique ; Gourdon, Jim C ; Hamadjida, Adjia ; Belliveau, Sébastien

We have previously discovered that the selective activation of metabotropic glutamate type 2 receptors (mGluR₂) and concurrent stimulation of metabotropic glutamate types 2 and 3 receptors (mGluR_2/3) enhance the anti-parkinsonian action of L-3,4-dihydroxyphenylalanine (L-DOPA). Here, we sought to determine the effects of the mGluR_2/3 orthosteric agonists LY-354,740 and LY-404,039, as well as the effects of the mGluR₂ positive allosteric modulators LY-487,379 and CBiPES on the range of movement, bradykinesia, posture and alertness as adjuncts to L-DOPA. Ten 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets entered 4 experimental streams: L-DOPA + LY-354,740 (vehicle, 0.1, 0.3 and 1 mg/kg), L-DOPA + LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg), L-DOPA + LY-487,379 (vehicle, 0.1, 1 and 10 mg/kg), L-DOPA + CBiPES (vehicle, 0.1, 1 and 10 mg/kg). For each molecule, treatments were randomised, and the range of movement, bradykinesia, posture and alertness were assessed by a blinded rater. None of the tested compounds significantly altered the global range of movement. LY-404,039 and CBiPES both reduced global bradykinesia, by up to 46% (both P < 0.05). LY-354,740, LY-404,039 and CBiPES each improved global posture by 35%, 44% and 39% (each P < 0.05), respectively. LY-404,039 and CBiPES both enhanced alertness by 54% (P < 0.05) and 79% (P < 0.01), respectively. LY-487,379 did not improve any of the parameters. Our results suggest that selective mGluR₂ positive allosteric modulation and combined mGluR_2/3 orthosteric stimulation might benefit bradykinesia, posture and alertness in PD when added to L-DOPA, which potentially represent novel therapeutic indications for molecules acting via these mechanisms.

01 Sep 2024·Pharmacology Biochemistry and Behavior

mGlu2/3 receptor agonist (LY354740) in anxiety

Review

Author: Schoepp, Darryle D

mGlu2/3 Receptors (LY354740) in Anxiety mGlu2/3 receptors when activated decrease glutamate excitation on limbic synapses involved in anxiety. The orally active agonist compound LY354740 (or prodrug LY544344) was active in animal and human models of stress/anxiety. Later clinical studies showed efficacy in generalized anxiety in patients, validating this mechanism clinically. However, the compound was terminated due to rodent seizures in long-term toxicology studies.

05 Aug 2024·Journal of General Physiology

ON and OFF starburst amacrine cells are controlled by distinct cholinergic pathways

Article

Author: Maruyama, Takuma ; Gangi, Mie ; Kaneda, Makoto ; Ishii, Toshiyuki

Cholinergic signaling in the retina is mediated by acetylcholine (ACh) released from starburst amacrine cells (SACs), which are key neurons for motion detection. SACs comprise ON and OFF subtypes, which morphologically show mirror symmetry to each other. Although many physiological studies on SACs have targeted ON cells only, the synaptic computation of ON and OFF SACs is assumed to be similar. Recent studies demonstrated that gene expression patterns and receptor types differed between ON and OFF SACs, suggesting differences in their functions. Here, we compared cholinergic signaling pathways between ON and OFF SACs in the mouse retina using the patch clamp technique. The application of ACh increased GABAergic feedback, observed as postsynaptic currents to SACs, in both ON and OFF SACs; however, the mode of GABAergic feedback differed. Nicotinic receptors mediated GABAergic feedback in both ON and OFF SACs, while muscarinic receptors mediated GABAergic feedback in ON SACs only in adults. Neither tetrodotoxin, which blocked action potentials, nor LY354740, which blocked neurotransmitter release from SACs, eliminated ACh-induced GABAergic feedback in SACs. These results suggest that ACh-induced GABAergic feedback in ON and OFF SACs is regulated by different feedback mechanisms in adults and mediated by non-spiking amacrine cells other than SACs.

100 Deals associated with Eglumegad

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KEGG	Wiki	ATC	Drug Bank
D08908	Eglumegad	-	-

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Indication	Highest Phase	Country/Location	Organization	Date
Panic Disorder	Preclinical	US	Eli Lilly & Co.	01 Nov 2005
Anxiety Disorders	Preclinical	GB	Eli Lilly & Co.	01 Feb 1998
Nicotine Dependence	Preclinical	US	Eli Lilly & Co.	01 Dec 1997
Psychotic Disorders	Preclinical	US	Eli Lilly & Co.	-
Schizophrenia	Preclinical	US	Eli Lilly & Co.	-
Seizures	Preclinical	GB	Eli Lilly & Co.	-
Seizures	Preclinical	US	Eli Lilly & Co.	-

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