We have cloned and sequenced a novel cytochrome P450 (CYP) designated CYP4X1. The CYP4X1 mRNA and protein are highly expressed in neurons of the CNS and is ~80% homologous between mouse, rat and human. Recently, we found abundant expression of CYP4X1 in the dorsal root ganglia (DRG). We have identified that CYP4X1 converts arachidonic acid (AA) to the four regioisomers of epoxyeicosatrienoic acids (EETs). Moreover, endogenous EETs injected into the periaqueductal grey area or given intraperitoneally show anti-nociceptive effects in the tail flick assay with greater potency than morphine. Furthermore, in collaboration with Dr. JR Falck (University of Texas, Southwestern), we have begun testing synthetic EET mimetics and have identified a lead compound that we will use in this Phase I application to provide evidence and rationale for the development in Phase II of commercial products as novel therapeutic strategies to alleviate acute/chronic pain. Phase I studies will focus on pharmacological profiling (dosage, route of administration, bioavailability, solubility, stability and metabolism) as well as define structure activity relationships by screening a focused chemical library. The data contained within this application are an exciting first step in the development of non-narcotic pain therapy. The very important identification of a new CYP gene with selectivity to the central and peripheral nervous system, coupled with the observation that EETs, products of CYP4X1, have anti-nociceptive effects gives us a unique opportunity in the area of pain management. This research team is poised to begin these studies as the tools, techniques and experience are in place to develop novel non-narcotic pain agents. Phase II studies will focus on larger animal models, sites of action as well as consideration of other applications (e.g. migraine). It is our intent to improve the current therapeutic options available for the treatment and management of pain. ? ? ?
