5-HT sub(4 receptor agonist mediated enhancement of cognitive function in vivo and amyloid precursor protein processing in vitro: A pharmacodynamic and pharmacokinetic assessment)

• Published in: Neuropharmacology 2011-08, Vol.61 (1-2), p.69-79
• Main Authors: Shen, Fei, Smith, Jacqueline AM, Chang, Ray, Bourdet, David L, Tsuruda, Pamela R, Obedencio, Glenmar P, Beattie, David T
• Format: Article
• Language: English
• ISSN: 0028-3908
• DOI: 10.1016/j.neuropharm.2011.02.026

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-HT sub(4 receptors are widely expressed in those CNS areas which receive substantial cholinergic input and are involved in cognition. The ability of 5-HT) sub(4) receptor agonists to increase acetylcholine (ACh) release and reduce cognitive impairment in both animals and humans has been demonstrated. In addition, 5-HT sub(4 receptor agonist modulation of levels of the amyloid precursor protein (APP) derived peptides, soluble amyloid precursor protein (sAPP alpha ) and amyloid beta protein (A beta ) in the CNS has been reported. In this study, the preclinical properties of three structurally-distinct 5-HT) sub(4) 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-HT sub(4 receptor but could be discriminated on the basis of their agonist activity. In cAMP accumulation and sAPP alpha secretion assays using recombinant HEK293f-5-HT) sub(4)(d)-APP sub(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-HT) sub(4) 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-HT sub(4 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-HT) sub(4) receptor agonists in the treatment of AD. In