Systems pharmacology modeling in neuroscience: Prediction and outcome of PF-04995274, a 5-HT4 partial agonist, in a clinical scopolamine impairment trial

• DOI: 10.4236/aad.2013.23012
• Publication Date: 2013-09-26T05:56:03Z
• Authors: Timothy Nicholas; Sridhar Duvvuri; Claire Leurent; David Raunig; Tracey Rapp; Phil Iredale; Carolyn Rowinski; Robert Carr; Patrick Roberts; Athan Spiros; Hugo Geerts
• Keywords: Scopolamine; 5-HT4 receptor; Clinical Pharmacology

Background: 5-HT 4 receptors in cortex and hippocampus area are considered as a possible target for modulation of cognitive functions Alzheimer's disease (AD).A systems pharmacology approach was adopted to evaluate the potential providing beneficial effects on cognition AD.Methods: A serotonergic synaptic cleft model developed by integrating serotonin firing, release, half-life, drug/tracer properties (affinity agonism) inputs activity output.The calibrated using both vivo data free levels preclinical models human imaging data.The further expanded other neurontransmitter incorporated into computer-based cortical network which implemented physiology 12 different membrane CNS targets.A biophysically realistic, multi-compartment 80 pyramidal cells 40 interneurons reported working memory tasks healthy humans schizophrenia patients.Model output duration firing response an external stimulus.Alzheimer's (AD) pathology, particular synapse neuronal cell loss addition cholinergic deficits, align with natural clinical progression.The used provide insights effect activation prospectively simulate PF-04995274, partial agonist, scopolamine-reversal trial subjects.Results: The suggested agonism memory.The also projected no or exacerbation scopolamine impairment low intrinsic agonists, supported subsequent outcome.The prediction strongly suggests that agonists high may have AD patients.