Comparison of the D₁ dopamine full agonists, dihydrexidine and doxanthrine, in the 6-OHDA rat model of Parkinson's disease.
BACKGROUND
Preclinical evidence indicates that D₁ dopamine receptor full agonists have potential as therapeutic agents for a variety of neurological conditions. Dihydrexidine (DHX) was the first high potency selective D₁ 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 D₁ dopamine receptor.


OBJECTIVE
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.


CONCLUSIONS
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.
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy and Integrative Neuroscience Program, Purdue University, West Lafayette, IN 47907, USA.
John D
JD
McCorvy
Val J
VJ
Watts
David E
DE
Nichols
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000503:physiopathology; D010617:Phenanthridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects* / Q000378:metabolism
C516224:2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno(3,4-c)isoquinoline; D018491:Dopamine Agonists; D010617:Phenanthridines; D017447:Receptors, Dopamine D1; C061532:dihydrexidine