Molecular Mechanisms of Desensitization Underlying the Differential Effects of Formyl Peptide Receptor 2 Agonists on Cardiac Structure-Function Post Myocardial Infarction.

Formyl peptide receptor 2 (FPR2) plays an integral role in the transition of macrophages from a pro-inflammatory program to one that is pro-resolving. FPR2-mediated stimulation of resolution post myocardial infarction has demonstrated efficacy in rodent models and is hypothesized to reduce progression into heart failure. FPR2 agonists that promote long-lasting receptor internalization can lead to persistent desensitization and diminished therapeutic benefits.

Discovery of PF-00217830: aryl piperazine napthyridinones as D2 partial agonists for schizophrenia and bipolar disorder.

The synthesis and structure-activity relationship (SAR) of a novel series of aryl piperazine napthyridinone D(2) partial agonists is described. Our goal was to optimize the affinities for the D(2), 5-HT(2A) and 5-HT(1A) receptors, such that the D(2)/5-HT(2A) ratio was greater than 5 to ensure maximal occupancy of these receptors when the D(2) occupancy reached efficacious levels. This strategy led to identification of PF-00217830 (2) with robust inhibition of sLMA (MED=0.

Cytoskeletal protein degradation and neurodegeneration evolves differently in males and females following experimental head injury.

The resulting neuropathological degeneration that occurs following a traumatic brain injury (TBI) is a consequence of both immediate and secondary neurochemical sequelae. Proteolysis of cytoskeletal proteins, triggered by calcium-mediated events, is believed to be a particularly significant contributor to TBI-induced neuronal death. To date, efforts to associate cytoskeletal degradation and neurodegeneration in TBI have been primarily qualitative or semiquantitative.