Delving into the Latest Updates on LY-2828360 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

CB2

Mechanism

CB2 agonists(Cannabinoid CB2 receptor agonists)

Therapeutic Areas

Immune System DiseasesSkin and Musculoskeletal Diseases

Active Indication-

Inactive Indication

Osteoarthritis, Knee

Originator Organization

Eli Lilly & Co.

Active Organization-

Inactive Organization

Eli Lilly & Co.

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC22H27ClN6O

InChIKeyUCMNDPDJRSEZPL-UHFFFAOYSA-N

CAS Registry1231220-79-3

Cannabinoid CB₂ agonists show therapeutic efficacy without unwanted CB₁-mediated side effects. The G protein-biased CB₂ receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks development of morphine tolerance in this model. However, the cell types involved in this phenomenon are unknown and whether this therapeutic profile is observed in female mice has never been investigated. We used conditional deletion of CB₂ receptors to determine the cell population(s) mediating the anti-allodynic and morphine-sparing effects of CB₂ agonists. Anti-allodynic effects of structurally distinct CB₂ agonists (LY2828360 and AM1710) were present in paclitaxel-treated CB₂^f/f mice and in mice lacking CB₂ receptors in CX3CR1 expressing microglia/macrophages (CX3CR1^CRE/+; CB₂^f/f), but were absent in mice lacking CB₂ receptors in peripheral sensory neurons (Advillin^CRE/+; CB₂^f/f). The morphine-sparing effect of LY28282360 occurred in a sexually-dimorphic manner, being present in male, but not female, mice. LY2828360 treatment (3 mg/kg per day i.p. x 12 days) blocked the development of morphine tolerance in male CB₂^f/f and CX3CR1^CRE/+; CB₂^f/f mice with established paclitaxel-induced neuropathy but was absent in male (or female) Advillin^CRE/+; CB₂^f/f mice. Co-administration of morphine with a low dose of LY2828360 (0.1 mg/kg per day i.p. x 6 days) reversed morphine tolerance in paclitaxel-treated male CB₂^f/f mice, but not Advillin^CRE/+; CB₂^f/f mice of either sex. LY2828360 (3 mg/kg per day i.p. x 8 days) delayed, but did not prevent, the development of paclitaxel-induced mechanical or cold allodynia in either CB₂^f/f or CX3CR1^CRE/+; CB₂^f/f mice of either sex. Our findings have potential clinical implications.

01 Feb 2024·Chemosphere

Interacting with luteinizing hormone receptor provides a new elucidation of the mechanism of anti-androgenicity of bisphenol S

Article

Author: Zhang, Xiaorong ; Zhang, Zhenzhong ; Shi, Yijiao ; Wang, Jun ; Ru, Shaoguo ; Zhang, Xinda ; Tian, Hua

Bisphenol S (BPS) exhibited inhibitory effects on androgen synthesis, but its target of action remains unclear. We investigated the effects of BPS exposure at environmentally relevant concentrations (1 μg/L, 10 μg/L and 100 μg/L) for 48 h on androgen synthesis in rat ovarian theca cells and explored the underlying mechanisms, target site and target molecule. The results showed that BPS exposure inhibited the transcript levels of steroidogenic genes and reduced the contents of androgen precursors, testosterone and dihydrotestosterone. BPS exposure decreased the phosphorylation levels of extracellular signal-related kinase 1/2 (ERK1/2), and the inhibitory effects of BPS on testosterone content and steroidogenic gene expression were blocked by ERK1/2 agonist LY2828360, suggesting that ERK1/2 signaling pathway mediates the inhibitory effects of BPS on androgen synthesis. BPS mainly accumulated on the cell membrane, impermeable BPS-bovine serum albumin exposure still inhibited androgen synthesis, BPS interacted with rat luteinizing hormone receptor (LHR) via formation of hydrogen bonds in the transmembrane region, and the inhibitory effects of BPS on ERK1/2 phosphorylation were blocked by luteinizing hormone (the natural agonist of LHR), indicating that LHR located on the cell membrane is the target of action of BPS. This paper provides a new elucidation of the mechanism of anti-androgenicity of BPS, especially for the non-genomic pathways.

01 Oct 2023·Neuropharmacology

Conditional deletion of CB2 cannabinoid receptors from peripheral sensory neurons eliminates CB2-mediated antinociceptive efficacy in a mouse model of carrageenan-induced inflammatory pain

Article

Author: Guenther, Kelsey G ; Mackie, Ken ; Xu, Zhili ; Hohmann, Andrea G ; Hillard, Cecilia J ; Romero, Julian

CB₂ cannabinoid receptor agonists suppress pathological pain in animal models and lack unwanted side effects commonly associated with direct activation of CB₁ receptors. However, the types of pain most responsive to CB₂ agonists are incompletely understood and cell types which underlie CB₂-mediated therapeutic efficacy remain largely unknown. We previously reported that the CB₂ receptor agonist LY2828360 reduced neuropathic nociception induced by toxic challenge with chemotherapeutic and anti-retroviral agents in mice. Whether these findings generalize to models of inflammatory pain is not known. Here we show that LY2828360 (10 mg/kg i.p.) reversed the maintenance of carrageenan-induced mechanical allodynia in female mice. Anti-allodynic efficacy was fully preserved in global CB₁ knock out (KO) mice but absent in CB₂ KO mice. The anti-allodynic efficacy of LY2828360 was absent in conditional KO (cKO) mice lacking CB₂ receptors in peripheral sensory neurons (Advillin^CRE/+; CB₂^f/f) and preserved in cKO mice lacking CB₂ receptors in microglia/macrophages expressing C-X3-C Motif Chemokine Receptor 1 (CX3CR1^CRE/+; CB₂^f/f). Intraplantar administration of LY2828360 (30 μg i.pl.) reversed carrageenan-induced mechanical allodynia in CB₂^f/f but not Advillin^CRE/+; CB₂^f/f mice of both sexes. Thus, CB₂ receptors in peripheral sensory neurons likely underlie the therapeutic effects of LY2828360 injection in the paw. Lastly, qRT-PCR analyses revealed that LY2828360 reduced carrageenan-induced increases in IL-1β and IL-10 mRNA in paw skin. Our results suggest that LY2828360 suppresses inflammatory nociception in mice through a neuronal CB₂-dependent mechanism that requires peripheral sensory neuron CB₂ receptors and suggest that the clinical applications of LY2828360 as an anti-hyperalgesic agent should be re-evaluated.

100 Deals associated with LY-2828360

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16074

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Osteoarthritis, Knee	Phase 2	DK	Eli Lilly & Co.	01 Mar 2011

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01319929 (CTgov)	Phase 2	Osteoarthritis, Knee	39	LY2828360 (80 mg LY2828360)	rssvihakty(xemxreewnl) = cichzqqemm davhfkwxay (cshvcswjda, cbhloatqlz - luexjxrrvp) View more	-	19 May 2020
				placebo (Placebo)	rssvihakty(xemxreewnl) = tbnuhgcnps davhfkwxay (cshvcswjda, cxvsnmxmpk - pyvoxpsmfw) View more