Design of Small Non-Peptidic Ligands That Alter Heteromerization between Cannabinoid CB1 and Serotonin 5HT2A Receptors DOI Creative Commons
Minos‐Timotheos Matsoukas, Marc Ciruela-Jardí, Maria Gallo

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 26, 2024

Activation of cannabinoid CB1 receptors (CB1R) by agonists induces analgesia but also cognitive impairment through the heteromer formed between CB1R and serotonin 5HT2A receptor (5HT2AR). This side effect poses a serious drawback in therapeutic use cannabis for pain alleviation. Peptides designed from transmembrane helices CB1R, which are predicted to bind 5HT2AR alter stability CB1R-5HT2AR heteromer, have been shown avert agonist-induced while preserving analgesia. Using these peptides as templates, we now nonpeptidic small molecules that prevent heteromerization bimolecular fluorescence complementation assays heteromerization-dependent allosteric modulations cell signaling experiments. These results provide proof-of-principle design optimized ligand-based disruptors opening new perspectives vivo studies.

Language: Английский

Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling DOI Creative Commons
Gemma Navarro, Marc Gómez‐Autet, Paula Morales

et al.

Pharmacological Research, Journal Year: 2024, Volume and Issue: 208, P. 107363 - 107363

Published: Aug. 23, 2024

G protein-coupled receptors (GPCRs) exist within a landscape of interconvertible conformational states and in dynamic equilibrium between monomers higher-order oligomers, both influenced by ligand binding. Here, we show that homobivalent formed equal chromenopyrazole moieties as pharmacophores, connected 14 methylene units, can modulate the dynamics cannabinoid CB

Language: Английский

Citations

19
Two-Step Cell Death Induction by the New 2-Arachidonoyl Glycerol Analog and Its Modulation by Lysophosphatidylinositol in Human Breast Cancer Cells DOI Open Access
Mikhail Akimov, N. M. Gretskaya, Evgenia I. Gorbacheva

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(2), P. 820 - 820

Published: Jan. 19, 2025

2-arachnadoyl glycerol (2-AG) is one of the most common endocannabinoid molecules with anti-proliferative, cytotoxic, and pro-proliferative effects on different types tumors. Typically, it induces cell death via cannabinoid receptor 1/2 (CB1/CB2)-linked ceramide production. In breast cancer, counterbalanced by sphingosine-1-phosphate, thus mechanisms 2-AG influence proliferation are poorly understood. We evaluated mechanism anti-proliferative action lysophaosphatidylinositol (LPI) in six human cancer lines tumor degree (MCF-10A, MCF-7, BT-474, BT-20, SK-BR-3, MDA-MB-231) using resazurin test, inhibitor, blocker, anti-oxidant analysis, siRNA interference. To avoid acyl migration 2-AG, we replaced analog 2-arachidonoyl-1,3-difluoropropanol (2-ADFP) newly synthesized us. Using a molecular docking approach, showed that at CB2 receptor, 2-ADFP were very close to each other. However, demonstrated stronger affinity towards CB1 antagonist-bound conformation. was all tested. The toxicity enhanced LPI. activity reduced or prevented vanilloid 1 (TRPV1) blockers, inositol triphosphate CREB, cyclooxygenase 2 addition. Together literature data, these results indicate CB2- TRPV1-dependent COX-2 induction concomitant oxidized molecule’s metabolites.

Language: Английский

Citations

0
Attributes novel drug candidate: Constitutive GPCR signal bias mediated by purinergic receptors DOI

Li Yin,

Kexin Ni,

Tianqi Mao

et al.

Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 108802 - 108802

Published: Jan. 1, 2025

Language: Английский

Citations

0
Homodimerization of CB2cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling DOI Open Access
Gemma Navarro, Marc Gómez‐Autet, Paula Morales

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 11, 2024

ABSTRACT G protein-coupled receptors (GPCRs) exist within a landscape of interconvertible conformational states and in dynamic equilibrium between monomers higher-order oligomers, both influenced by ligand binding. Here, we have shown that homobivalent formed equal chromenopyrazole moieties as pharmacophores, connected 14 methylene units, can modulate the dynamics cannabinoid CB 2 receptor (CB R) homodimerization simultaneously binding protomers R-CB R homodimer. Computational pharmacological experimentals showed one pharmacophores binds to orthosteric site protomer, other pharmacophore membrane-oriented pocket transmembranes 1 7 partner protomer. This provides unique properties, such increased potency i recruitment β-arrestin. Thus, modulating dimerization dynamics, it may be possible fine-tune activity with potentially improved therapeutic outcomes. HIGHLIGHTS A (PM369) modulates PM369 protomer complementary, membrane-facing, triggers via TM 1/7 interface properties potentiates signaling, β-arrestin These results highlight new approaches control GPCR signaling GRAPHICAL

Language: Английский

Citations

0
The Two-Step Cell Death Induction by the New 2-Arachidonoyl Glycerol Analog and its Modulation by Lysophosphatidylino-sitol in Human Breast Cancer Cells DOI Open Access
Mikhail Akimov, N. M. Gretskaya, Evgenia I. Gorbacheva

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 1, 2024

Abstract 2-arachnadoyl glycerol (2-AG) is one of the most common endocannabinoid molecules with antiproliferative, cytotoxic and pro-proliferative effects on different types tumors. Typically, it induces cell death via CB1/CB2-linked ceramide production. In breast cancer, counterbalanced by sphingosine-1-phosphate, thus mechanisms 2-AG influence proliferation are poorly understood. this paper, we evaluated mechanism induction LPI in 6 human cancer lines tumor degree using a novel analog, 2-arachidonoyl-difluoropropanol (2-ADFP). 2-ADFP induced CB2 TRPV1-dependent COX-2 oxidized metabolites The activity was enhanced LPI.

Language: Английский

Citations

0
Design of Small Non-Peptidic Ligands That Alter Heteromerization between Cannabinoid CB1 and Serotonin 5HT2A Receptors DOI Creative Commons
Minos‐Timotheos Matsoukas, Marc Ciruela-Jardí, Maria Gallo

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 26, 2024

Activation of cannabinoid CB1 receptors (CB1R) by agonists induces analgesia but also cognitive impairment through the heteromer formed between CB1R and serotonin 5HT2A receptor (5HT2AR). This side effect poses a serious drawback in therapeutic use cannabis for pain alleviation. Peptides designed from transmembrane helices CB1R, which are predicted to bind 5HT2AR alter stability CB1R-5HT2AR heteromer, have been shown avert agonist-induced while preserving analgesia. Using these peptides as templates, we now nonpeptidic small molecules that prevent heteromerization bimolecular fluorescence complementation assays heteromerization-dependent allosteric modulations cell signaling experiments. These results provide proof-of-principle design optimized ligand-based disruptors opening new perspectives vivo studies.

Language: Английский

Citations

0