5-HT4 receptor agonist mediated enhancement of cognitive function in vivo and amyloid precursor protein processing in vitro: A pharmacodynamic and pharmacokinetic assessment

There remains an urgent need for therapeutic agents that provide improved symptomatic treatment and attenuate disease progression in patients with Alzheimer's disease (AD). 5-HT4 receptors are widely expressed in those CNS areas which receive substantial cholinergic input and are involved in cognition. The ability of 5-HT4 receptor agonists to increase acetylcholine (ACh) release and reduce cognitive impairment in both animals and humans has been demonstrated. In addition, 5-HT4 receptor agonist modulation of levels of the amyloid precursor protein (APP) derived peptides, soluble amyloid precursor protein (sAPP alpha) and amyloid beta protein (AP) in the CNS has been reported. In this study, the preclinical properties of three structurally-distinct 5-HT4 receptor selective agonists, PRX-03140, velusetrag and TD-8954, were studied to assess their potential for symptomatic and disease-modifying benefit in the treatment of AD. All three compounds exhibited high affinity for the rat 5-HT4 receptor but could be discriminated on the basis of their agonist activity. In cAMP accumulation and sAPP alpha. secretion assays using recombinant HEK293f-5-HT4(d)-APP(695) cells, velusetrag and TD-8954 were potent, full agonists, relative to 5-HT, whereas PRX-03140 was a partial agonist (intrinsic activity 18%, relative to 5-HT). In a guinea pig colon isolated tissue preparation, TD-8954 exhibited lower intrinsic activity than velusetrag. and PRX-03140 had negligible agonist activity. In the rat Morris water maze (MWM) cognition test, velusetrag and TD-8954 (0.1 mg/kg), but not PRX-03140 (0.03-1 mg/kg), significantly reversed the scopolamine-induced spatial learning deficit via activation of 5-HT4 receptors. Coadministration of subefficacious doses of the acetylcholinesterase inhibitor (AChEi), donepezil (0.1 mg/kg, i.p.), and either velusetrag or TD-8954 (0.01 mg/kg i.p.) resulted in reversal of the scopolamine-induced cognitive deficit Pharmacokinetic data indicated that the CNS penetration for all three 5-HT4 receptor agonists was relatively low. However, the pharmacodynamic pharmacokinetic relationships in the MWM model for velusetrag and TD-8954 were consistent with their respective receptor pharmacology (binding affinity and intrinsic efficacy) and CNS penetration properties. Collectively, these findings support a potential role for potent and efficacious 5-HT4 receptor agonists in the treatment of AD. (C) 2011 Elsevier Ltd. All rights reserved.