dihydrexidine and Disease-Models--Animal

Levodopa is the standard-of-care for Parkinson's disease, but continued loss of dopamine neurons with disease progression decreases its bioconversion to dopamine, leading to increased side effects and decreased efficacy. In theory, dopamine agonists could equal levodopa, but no approved oral "dopamine agonist" matches the efficacy of levodopa. There are consistent data in both primate models and in Parkinson's disease showing that selective high intrinsic activity D

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Brain; Bromocriptine; Chlorocebus aethiops; Disease Models, Animal; Dopamine Agonists; Levodopa; Male; Motor Activity; Parkinsonian Disorders; Phenanthridines; Receptors, Dopamine D1; Receptors, Dopamine D2

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.. 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.. 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.. 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.

Topics: Administration, Oral; Animals; 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