Moser_2002_J.Pharmacol.Exp.Ther_302_731

Reference

Title : SL65.0155, A Novel 5-Hydroxytryptamine(4) Receptor Partial Agonist with Potent Cognition-Enhancing Properties - Moser_2002_J.Pharmacol.Exp.Ther_302_731
Author(s) : Moser PC , Bergis OE , Jegham S , Lochead A , Duconseille E , Terranova JP , Caille D , Berque-Bestel I , Lezoualc'h F , Fischmeister R , Dumuis A , Bockaert J , George P , Soubrie P , Scatton B
Ref : Journal of Pharmacology & Experimental Therapeutics , 302 :731 , 2002
Abstract :

SL65.0155 [5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[1-(2-phenyl ethyl)-4-piperidinyl]-1,3,4-oxadiazol-2(3H)-one monohydrochloride] is a novel benzodioxanoxadiazolone compound with high affinity for human 5-hydroxytryptamine (5-HT)(4) receptors (K(i) of 0.6 nM) and good selectivity (greater than 100-fold for all other receptors tested). In cells expressing the 5-HT(4(b)) and 5-HT(4(e)) splice variants, SL65.0155 acted as a partial agonist, stimulating cAMP production with a maximal effect of 40 to 50% of serotonin. However, in the rat esophagus preparation, SL65.0155 acted as a 5-HT(4) antagonist with a pK(b) of 8.81. In addition, SL65.0155 potently improved performance in several tests of learning and memory. In the object recognition task, it improved retention at 24 h when administered i.p. or p.o. (0.001-0.1 mg/kg). This effect was antagonized by the 5-HT(4) antagonist SDZ 205,557, itself without effect, demonstrating that the promnesic effects of SL65.0155 are mediated by 5-HT(4) agonism. SL65.0155 also reversed the cognitive deficits of aged rats in the linear maze task and the scopolamine-induced deficit of mice in the water maze task. Furthermore, the combined administration of an inactive dose of SL65.0155 with the cholinesterase inhibitor rivastigmine resulted in a significant promnesic effect, suggesting a synergistic interaction. SL65.0155 was devoid of unwanted cardiovascular, gastrointestinal, or central nervous system effects with doses up to more than 100-fold higher than those active in the cognitive tests. These results characterize SL65.0155 as a novel promnesic agent acting via 5-HT(4) receptors, with an excellent preclinical profile. Its broad range of activity in cognitive tests and synergism with cholinesterase inhibitors suggest that SL65.0155 represents a promising new agent for the treatment of dementia.

PubMedSearch : Moser_2002_J.Pharmacol.Exp.Ther_302_731
PubMedID: 12130738

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Citations formats

Moser PC, Bergis OE, Jegham S, Lochead A, Duconseille E, Terranova JP, Caille D, Berque-Bestel I, Lezoualc'h F, Fischmeister R, Dumuis A, Bockaert J, George P, Soubrie P, Scatton B (2002)
SL65.0155, A Novel 5-Hydroxytryptamine(4) Receptor Partial Agonist with Potent Cognition-Enhancing Properties
Journal of Pharmacology & Experimental Therapeutics 302 :731

Moser PC, Bergis OE, Jegham S, Lochead A, Duconseille E, Terranova JP, Caille D, Berque-Bestel I, Lezoualc'h F, Fischmeister R, Dumuis A, Bockaert J, George P, Soubrie P, Scatton B (2002)
Journal of Pharmacology & Experimental Therapeutics 302 :731