Comparison of the D₁ dopamine full agonists, dihydrexidine and doxanthrine, in the 6-OHDA rat model of Parkinson's disease. Psychopharmacology (Berl) 2012 Jul;222(1):81-7
Date
01/10/2012Pubmed ID
22222862DOI
10.1007/s00213-011-2625-5Scopus ID
2-s2.0-84861840044 (requires institutional sign-in at Scopus site) 7 CitationsAbstract
RATIONALE: 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.
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.
Author List
McCorvy JD, Watts VJ, Nichols DEAuthor
John McCorvy PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Administration, OralAnimals
Area Under Curve
Disease Models, Animal
Dopamine Agonists
Dose-Response Relationship, Drug
Injections, Intraperitoneal
Male
Motor Activity
Parkinsonian Disorders
Phenanthridines
Rats
Rats, Sprague-Dawley
Receptors, Dopamine D1
