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5-HT(4) receptor agonist mediated enhancement of cognitive function in vivo and amyloid precursor protein processing

Fei Shen1, Jacqueline A M Smith, Ray Chang

  • 1Department of Pharmacology, Theravance Inc., 901 Gateway Boulevard, South San Francisco, CA 94080, USA. fshen@theravance.com

Neuropharmacology
|March 12, 2011
PubMed

Insights

Potent 5-HT(4) receptor agonists, velusetrag and TD-8954, show promise for Alzheimer's disease (AD) treatment by improving cognition. These compounds, along with PRX-03140, were evaluated for their potential to offer symptomatic and disease-modifying benefits in AD therapy.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Drug Discovery

Background:

  • Alzheimer's disease (AD) urgently requires new therapies for symptomatic relief and disease modification.
  • 5-HT(4) receptors are crucial in cognitive functions and are targets for modulating acetylcholine (ACh) release.
  • Previous research suggests 5-HT(4) receptor agonists can influence amyloid precursor protein (APP) derived peptides.

Purpose of the Study:

  • To evaluate the preclinical potential of three distinct 5-HT(4) receptor agonists (PRX-03140, velusetrag, TD-8954) for AD treatment.
  • To assess their symptomatic and disease-modifying benefits.
  • To investigate their pharmacological profiles, including receptor affinity, efficacy, and effects on cognition.

Main Methods:

  • Assessed agonist activity using cAMP accumulation and sAPPα secretion assays in cell lines.
  • Evaluated intrinsic activity in guinea pig colon preparations.
  • Tested cognitive effects in the rat Morris water maze (MWM) model after scopolamine-induced deficit.
  • Examined synergistic effects with donepezil (an acetylcholinesterase inhibitor).
  • Analyzed pharmacokinetic properties, including CNS penetration.

Main Results:

  • Velusetrag and TD-8954 demonstrated high affinity and acted as potent, full 5-HT(4) receptor agonists, while PRX-03140 was a partial agonist.
  • Velusetrag and TD-8954 significantly reversed scopolamine-induced spatial learning deficits in the MWM, unlike PRX-03140.
  • Combined administration of sub-therapeutic doses of velusetrag or TD-8954 with donepezil also reversed cognitive deficits.
  • Pharmacokinetic analysis revealed relatively low CNS penetration for all compounds, but pharmacodynamic-pharmacokinetic relationships supported the efficacy of velusetrag and TD-8954.

Conclusions:

  • Potent and efficacious 5-HT(4) receptor agonists, particularly velusetrag and TD-8954, show significant potential for treating Alzheimer's disease.
  • These agonists may offer both symptomatic relief and potentially disease-modifying benefits.
  • Further research into 5-HT(4) receptor agonists is warranted for AD therapeutic development.

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