Xoc Pharmaceuticals (Xoc) is developing XC130-A10H, a novel molecule, for treatment of Parkinson’s disease (PD). Key in vitro safety and efficacy indicators are assessed and contrasted with the reference dopamine agonist compounds, lisuride and pergolide.  

Pergolide was a useful dopamine agonist monotherapy and as part of levodopa-sparing regimens before being withdrawn from the market due to fibrosis concerns related to its 5-HT_2B agonistic character. Stocchi et al (Brain (2002), 125, 2058-2066) demonstrated that patients receiving lisuride infusions experienced a significant reduction in both motor fluctuations and dyskinesia over the 4-year study duration when compared to patients on standard dopaminergic therapies. In addition, the mean UPDRS scores remained the same for the lisuride-levodopa patients but deteriorated in patients on levodopa only. However, due to its short half-life and 5-HT_2B agonistic character, lisuride was not a suitable replacement for pergolide.

XC130-A10H is being developed as an orally administered partial dopamine agonist for the treatment of Parkinson’s disease with the potential to provide therapy similar to the ergot alkaloid dopamine agonists.  XC130-A10H is engineered to delay the commencement of levodopa administration, lower the levodopa dose for late stage patients, and avoid undesirable side effects common to the existing dopamine agonist therapies.

State-of-the-art biological assays using human recombinant G protein-coupled receptors were used to determine binding (% activation/inhibition), activity (EC₅₀/IC₅₀), and half-life (based on k_on/k_off constants).

XC130-A10H is a long-acting partial D₂ agonist with a potency similar to lisuride, while it is also an antagonist at receptors that have been linked to important side effects associated with historical dopaminergic agents: D₃ (obsessive compulsive behavior), a_1A and 5-HT_1B (vasoconstriction), 5-HT_2A (psychosis) and 5-HT_2B (valvulopathy). 

The in vitro receptor activity profile shows that XC130-A10H could represent an important addition to the therapeutic armamentarium throughout the time course of Parkinson’s disease.