Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

作者：Lecoutey Cedric; Hedou Damien; Freret Thomas; Giannoni Patrizia; Gaven Florence; Since Marc; Bouet Valentine; Ballandonne Celine; Corvaisier Sophie; Freon Aurelie Malzert; Mignani Serge; Cresteil Thierry; Boulouard Michel; Claeysen Sylvie; Rochais Christophe^*; Dallemagne Patrick

来源：Proceedings of the National Academy of Sciences of the United States of America, 2014, 111(36): E3825-E3830.

DOI：10.1073/pnas.1410315111/-/DCSupplemental

RS67333 is a partial serotonin subtype 4 receptor (5-HT4R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-beta peptide leads to the secretion of the neurotrophic protein sAPP alpha. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer's disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitarget-directed ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT4R partial agonist (K-i = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC50 = 16 nM) that further promotes sAPPa release (EC50 = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment.

• 出版日期2014-9-9