Vol. 302, Issue 2, 731-741, August 2002

SL65.0155, A Novel 5-Hydroxytryptamine₄ Receptor Partial Agonist with Potent Cognition-Enhancing Properties

Paul C. Moser, Olivier E. Bergis, Samir Jegham, Alistair Lochead, Elee Duconseille, Jean-Paul Terranova, Dominique Caille, Isabelle Berque-Bestel, Frank Lezoualc'h, Rodolphe Fischmeister, Aline Dumuis, Joel Bockaert, Pascal George, Philippe Soubrié and Bernard Scatton

Sanofi-Synthelabo Recherche, Bagneux, France (P.C.M., O.E.B., A.L., E.D., P.G., B.S.); Sanofi-Synthelabo Recherche, Rueil-Malmaison, France (D.C.); Sanofi-Synthelabo Recherche, Montpellier, France (S.J., J.-P.T., P.S.); Laboratoire de Reconnaissance Moléculaire et Cellulaire, BIOCIS, UPRES A 8076, IFR-75, Faculté de Pharmacie, Châtenay-Malabry, France (I.B.-B.); Laboratoire de Cardiologie Cellulaire et Moléculaire, Institut National de la Santé et de la Recherche Medicale, U-446, Faculté de Pharmacie, Châtenay-Malabry, France (F.L., R.F.); and Laboratoire des Mécanismes Moléculaires des Communications Cellulaires, Centre National de la Recherche Scientifique UPR 9023, Montpellier, France (A.D., J.B.)

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-HT₄ 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-HT₄ antagonist SDZ 205,557, itself without effect, demonstrating that the promnesic effects of SL65.0155 are mediated by 5-HT₄ 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-HT₄ 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.