SL65.0155, a novel 5-hydroxytryptamine(4) receptor partial agonist with potent cognition-enhancing properties.
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.
Sanofi-Synthelabo Recherche, 31 avenue Paul Vaillant Couturier, 92220 Bagneux, France.
Paul C
PC
Moser
Olivier E
OE
Bergis
Samir
S
Jegham
Alistair
A
Lochead
Elee
E
Duconseille
Jean-Paul
JP
Terranova
Dominique
D
Caille
Isabelle
I
Berque-Bestel
Frank
F
Lezoualc'h
Rodolphe
R
Fischmeister
Aline
A
Dumuis
Joel
J
Bockaert
Pascal
P
George
Philippe
P
Soubrié
Bernard
B
Scatton
D017398:Alternative Splicing; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism*; D004146:Dioxanes / Q000494:pharmacology*; D004947:Esophagus / Q000187:drug effects / Q000502:physiology; D005769:Gastrointestinal Motility / Q000187:drug effects; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010069:Oxadiazoles / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D044422:Receptors, Serotonin, 5-HT4; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014162:Transfection
C464499:5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-(1-(2-phenylethyl)-4-piperidinyl)-1,3,4-oxadiazol-2(3H)-one; D004146:Dioxanes; D010069:Oxadiazoles; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D017366:Serotonin Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4; D000242:Cyclic AMP