Description
PF-04995274 is a partial agonist of the serotonin (5-HT) receptor subtypes 5-HT
4A, 5-HT
4B, 5-HT
4D, and 5-HT
4E (K
is = 0.36, 0.46, 0.15, and 0.32 nM, respectively, in a radioligand binding assay). It increases cAMP levels in HEK293 cells expressing 5-HT
4A, 5-HT
4B, 5-HT
4D, and 5-HT
4E receptors (EC
50s = 0.47, 0.36, 0.37, and 0.26 nM, respectively, for the human recombinant receptors). PF-04995274 decreases scopolamine-induced increases in the distance traveled in the Morris water maze in rats when administered at a dose of 0.032 mg/kg.
Uses
PF-04995274 is a potent, high-affinity, orally active and partial serotonin 4 receptor (5-HT4R) agonist. PF-04995274 has an EC50 range of 0.26-0.47 nM for human 5-HT4A/4B/4D/4E (Ki range of 0.15-0.46 nM), and has an EC50 range of 0.59-0.65 nM for rat 5-HT4S/4L/4E (Ki of 0.30 nM for rat 5-HT4S). PF-04995274 is brain penetrant and can be used for cognitive disorders associated with Alzheimer's disease[1][2][3].
in vivo
PF-04995274 (3-10 mg/kg; intravenous injection; for 17 days; male 129S6/SvEv mice) treatment results in prophylactic efficacy by attenuating learned fear and decreasing stress-induced depressive-like behavior[1].
| Animal Model: | Male 129S6/SvEv mice (7-8 weeks) treated with contextual fear conditioning (CFC) and forced swim test (FST)[1] |
| Dosage: | 3 mg/kg, 10 mg/kg |
| Administration: | Intravenous injection; for 17 days |
| Result: | Attenuated learned fear and decreased stress-induced depressive-like behavior.
|
References
[1] Chen BK, et al. Prophylactic efficacy of 5-HT4R agonists against stress. Neuropsychopharmacology. 2019 Oct 10. DOI:
10.1038/s41386-019-0540-3[2] Grimwood S, et al. Translational receptor occupancy for the 5-HT4 partial agonist PF-04995274 in rats, non-human primates and healthy volunteers. Alzheimer’s Dement: J Alzheimer’s Assoc. 2011;7:S653.
[3] Timothy Nicholas1, et al. Systems pharmacology modeling in neuroscience: Prediction and outcome of PF-04995274, a 5-HT4 partial agonist, in a clinical scopolamine impairment trial. Advances in Alzheimer's Disease. Vol.2 No.3(2013).
