Riluzole-Rasagiline Hybrids: Toward the Development of Multi-Target-Directed Ligands for Amyotrophic Lateral Sclerosis

Overview

Journal ACS Chem Neurosci

Publisher American Chemical Society

Specialty Neurology

Date 2022 Jul 22

PMID 35868251

Authors

Claudia Albertini

Alessandra Salerno

Silvia Atzeni

Elisa Uliassi

Francesca Massenzio

Annalisa Maruca

Roberta Rocca

Marko Mecava

Filomena S G Silva

Debora Mena

Pedro Valente

Ana I Duarte

Daniel Chavarria

Maicol Bissaro

Stefano Moro

Stephanie Federico

Giampiero Spalluto

Ondrej Soukup

Fernanda Borges

Stefano Alcaro

Barbara Monti

Paulo J Oliveira

Jose C Menendez

Maria Laura Bolognesi

Affiliations

Soon will be listed here.

Abstract

Polypharmacology is a new trend in amyotrophic lateral sclerosis (ALS) therapy and an effective way of addressing a multifactorial etiology involving excitotoxicity, mitochondrial dysfunction, oxidative stress, and microglial activation. Inspired by a reported clinical trial, we converted a riluzole ()-rasagiline () combination into single-molecule multi-target-directed ligands. By a ligand-based approach, the highly structurally integrated hybrids - were designed and synthesized. Through a target- and phenotypic-based screening pipeline, we identified hit compound . It showed monoamine oxidase A (MAO-A) inhibitory activity (IC = 6.9 μM) rationalized by studies as well as brain permeability. By using neuronal and non-neuronal cell models, including ALS-patient-derived cells, we disclosed for a neuroprotective/neuroinflammatory profile similar to that of the parent compounds and their combination. Furthermore, the unexpected MAO inhibitory activity of (IC = 8.7 μM) might add a piece to the puzzle of its anti-ALS molecular profile.

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