ORIGINAL INVESTIGATION Comparison of the D 1 dopamine full agonists, dihydrexidine and doxanthrine, in the 6-OHDA rat model of Parkinson's disease John D. McCorvy & Val J. Watts & David E. Nichols Received: 23 August 2011 / Accepted: 16 December 2011 / Published online: 6 January 2012 # Springer-Verlag 2012 Abstract Rationale Preclinical evidence indicates that D 1 dopamine receptor full agonists have potential as therapeutic agents for a variety of neurological conditions. Dihydrexidine (DHX) was the first high potency selective D 1 dopamine receptor full agonist and has been studied as a possible treatment for Parkinson's disease (PD). Recently, we discovered doxanthrine (DOX), an oxygen bioisostere of DHX that has even greater selectivity for the D 1 dopamine receptor. Objectives Using the unilateral 6-hydroxydopamine-lesioned rat model of PD, DOX and DHX were compared at several doses (0.625, 1.25, 2.5, or 5.0 mg/kg) for their ability to elicit contralateral rotation by either intraperitoneal injection or oral gavage. Results After intraperitoneal administration, both DOX and DHX showed robust contralateral rotation at doses of 2.5 and 5.0 mg/kg compared to vehicle. In addition, after intraperitoneal administration at doses of 2.5 and 5.0 mg/kg, DHX had a significantly longer duration of action than DOX (p <0.05). Areas under the curves (AUC) for DOX and DHX were not significantly different, however, indicating that DOX and DHX have similar potency after intraperitoneal administration. By contrast, after oral administration, 2.5 and 5.0 mg/kg of DOX produced significant contralateral rotations (p <0.05), whereas DHX showed no significant activity after oral administration of any dose. Conclusion These results demonstrate that although DHX and DOX have similar activity after intraperitoneal administration, DOX demonstrated greater activity after oral administration compared to DHX. Despite its catechol functionality, DOX may possess sufficient oral availability for development as a human therapeutic agent. Keywords Parkinson's disease . Dopamine D 1 receptor . Dihydrexidine . Doxanthrine . 6-Hydroxydopamine . Rat . Contralateral rotation Introduction Parkinson's disease (PD) is a progressive neurodegenerative condition that affects millions of people worldwide (Hickey and Stacy 2011). PD involves loss of motor control that includes symptoms such as a resting tremor, rigidity, bradykinesia, and postural instability (Rodriguez-Oroz et al. 2009) but also can include cognitive dysfunctions such as deficits in working memory (Lewis et al. 2003). The etiology of PD is still not well understood but most of the symptoms arise as a result of cell death in the substantia nigra (Foltynie et al. 2002), which provides dopaminergic input into the basal ganglia responsible for voluntary motor control. Although current therapies do not slow the progression of the disease or treat non-motor symptoms, the most effective long-term control of the motor symptoms is presently achieved using L-DOPA as a dopamine replacement therapy, which after several years of treatment can result in periodic “on-off” states that make PD therapy very difficult to manage (Fahn et al. 2004). The length of time that L-DOPA remains efficacious also is a severe limiting factor in PD therapy, where the progression of the disease can last for decades after diagnosis (Silver 2006). As a result of these problems with L-DOPA, initial monotherapy with dopamine receptor agonists active at J. D. McCorvy : V. J. Watts : D. E. Nichols (*) Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy and Integrative Neuroscience Program, Purdue University, West Lafayette, IN 47907, USA e-mail: drdave@purdue.edu Psychopharmacology (2012) 222:81–87 DOI 10.1007/s00213-011-2625-5