Objective/Rationale:
Estrogens modulate many cerebral functions such as mental state, mood, cognition and locomotion. Data indicate that estrogens may slow down the development and progression of PD in humans. The use of primary endogenous estrogen 17 beta-estradiol in treating PD is limited due to its feminizing effects and an increased risk of cancer. However, these side effects are believed to be associated with activation of the estrogen receptor alpha (ER-alpha), and thus compounds selective for the estrogen receptor beta (ER-beta) could potentially be used for chronic treatment in both men and women. ER-beta selective agonists have been shown to be neuroprotective and active in a number of preclinical models of various disorders associated with nonmotor behavioral symptoms of PD such as depression, cognition, inflammatory pain and neuropathic pain.
Project Description:
AC74131 is a selective ER-beta agonist discovered by ACADIA Pharmaceuticals that is highly potent in a range of in vivo models. Discovery efforts have generated analogs of AC74131 displaying in vivo activity after oral administration as well as reasonable brain exposure. The proposed studies will evaluate the efficacy of our lead ER-beta agonists in chemically induced rodent PD models (i.e. 6-hydroxydopamine and rotenone) focusing on neuroprotection, motor performance, cognition and sensorimotor gating. Subsequently, the best compounds after further optimization will be selected for pharmacokinetic studies in pre-clinical models of PD and for preliminary in vitro and in vivo toxicology studies.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The current studies will examine whether ER-beta agonists can alleviate motor and nonmotor deficits in rodent models of PD. Since these models produce a constellation of deficits that closely resemble the deficits seen in human PD patients, the ability to alleviate or reduce PD-like symptomology would suggest that ER-beta agonists might have therapeutic utility in the treatment of PD. Further, the proposed studies will begin to assess whether these compounds have suitable pharmacokinetic and toxicological profiles that might allow them to move toward early-stage human trials.
Anticipated Outcome:
We anticipate that ER-beta agonist treatment will reduce neuronal and behavioral deficits in rodent models of PD, and hope that the pharmacokinetic and toxicology studies will identify a suitable candidate for preclinical and clinical development.
Progress Report
Dr. Olsson and colleagues have found that their potent and selective class of estrogen receptor agonists, earlier reported to modulate inflammatory and neuropathic pain, produces a number of beneficial effects in male rodents with bilateral 6-hydroxydopamine lesions. Findings include positive effects on motor function, cognition and on sensory gating. These effects were seen in male rodents supporting the potential to treat both men and women. Interestingly, these effects were different from that of a nonselective estrogen agonist. Non-invasive administration of these compounds provides up to 77 percent bioavailability in rats.
Final Outcome
We have found that our potent and selective class of estrogen receptor agonists, earlier reported to modulate inflammatory and neuropathic pain, prevents damage to nigrostriatal dopamine neurons and produces a number of beneficial effects in male rats with bilateral 6-OHDA lesions. Findings include positive effects on motor function (rotorod, beam test, spontaneous locomotion), cognition (Novel Object Recognition) and on sensory gating (prepulse inhibition). These effects were seen in male rats supporting the potential to treat both men and women. Interestingly, these effects were different from that of the nonselective estrogen agonist, estradiol. Overall, a selected proof of concept molecule from this series of molecules has in addition to good activity in PD, inflammation, and pain models also good in vivo and in vitro PK and safety characteristics suitable for further drug development.