Five muscarinic acetylcholine receptor (mAChR) subtypes have been cloned (M1-M5) and all of them are expressed in the central nervous system, with the M1 receptor being the most predominant. M1 receptor agonism has been suggested to have a role in the treatment of Alzheimer's disease and cognitive impairment associated with schizophrenia. Xanomeline, an M1/M4 preferring orthosteric agonist could be a useful therapeutic agent. Unfortunately, its adverse effects and dose-limitations have removed it from consideration for long-term clinical use. More recently, a second generation of muscarinic M1-preferring receptor agonists has emerged. These compounds, such as AC-42, AC-260584, and 77-LH-28-1, interact at receptor binding sites topologically distinct from the acetylcholine binding pocket. In the quest for novel drug entities, in G protein-coupled receptors the bivalent ligand is a promising path to drug molecules that can effectively link two pharmacophores to achieve greater affinity and/or subtype selectivity. Bivalent compounds of xanomeline have already been reported to show an interesting profile of high binding affinity and strong agonist potency.1 Therefore, we designed and prepared a series of heterobivalent ligands formed by xanomeline, an orthosteric agonist, and 77-LH-28-1, an allosteric agonist, connected by an aliphatic spacer of variable length, and homobivalent ligands of 77-LH-28-1. All the novel compounds were evaluated by binding assays.

NOVEL BIVALENT LIGANDS OF XANOMELINE AND 77-LH-28-1 AS POTENTIAL M1 MUSCARINIC AGONISTS

BONIFAZI, ALESSANDRO;DEL BELLO, FABIO;GIANNELLA, Mario;MAMMOLI, VALERIO;PIGINI, Maria;PIERGENTILI, Alessandro;QUAGLIA, Wilma;
2013-01-01

Abstract

Five muscarinic acetylcholine receptor (mAChR) subtypes have been cloned (M1-M5) and all of them are expressed in the central nervous system, with the M1 receptor being the most predominant. M1 receptor agonism has been suggested to have a role in the treatment of Alzheimer's disease and cognitive impairment associated with schizophrenia. Xanomeline, an M1/M4 preferring orthosteric agonist could be a useful therapeutic agent. Unfortunately, its adverse effects and dose-limitations have removed it from consideration for long-term clinical use. More recently, a second generation of muscarinic M1-preferring receptor agonists has emerged. These compounds, such as AC-42, AC-260584, and 77-LH-28-1, interact at receptor binding sites topologically distinct from the acetylcholine binding pocket. In the quest for novel drug entities, in G protein-coupled receptors the bivalent ligand is a promising path to drug molecules that can effectively link two pharmacophores to achieve greater affinity and/or subtype selectivity. Bivalent compounds of xanomeline have already been reported to show an interesting profile of high binding affinity and strong agonist potency.1 Therefore, we designed and prepared a series of heterobivalent ligands formed by xanomeline, an orthosteric agonist, and 77-LH-28-1, an allosteric agonist, connected by an aliphatic spacer of variable length, and homobivalent ligands of 77-LH-28-1. All the novel compounds were evaluated by binding assays.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/369184
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