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 scopolamineinduced 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.Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive decline, debilitating behavioral impairment, and ultimately death. Neurofibrillary tangles and amyloid plaques are the pathological hallmarks of this disease, which is also characterized by a dramatic loss of cholinergic neurons in brain regions involved in higher cognitive functions. It is widely accepted that the loss of cholinergic markers is one of the major neurochemical deficits in AD and that this deficit correlates well with loss of cognitive abilities (Bierer et al., 1995;Palmer, 1996). Despite this, cholinergic therapies, such as inhibitors of acetylcholinesterase, have had only partial success (e.g., Volger, 1991), possibly due to the multifactorial nature of the deficits and poorly understood etiology of AD. Thus, there is a major need for novel therapeutic approaches that can alleviate the symptoms of the disease.In addition to the cholinergic deficit, loss of several other neurotransmitter systems has been reported in AD, including norepinephrine, dopamine (see Gottfries, 1990 for a review), and 5-hydroxytryptamine (5-HT) (Palmer, 1996; MeltArticle, publicat...
