dihydrexidine and Parkinsonian-Disorders

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

Selective D(1) dopamine receptor agonists exert antiparkinsonian effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson's disease and in human Parkinson's disease. Motor impairment in idiopathic Parkinson's disease progresses from mild to severe, but the therapeutic potential of D(1) dopamine receptor agonists in early and advanced stages of parkinsonism is not known. To compare the effectiveness of D(1) agonists at different levels of impairment, we developed a model of mild and advanced parkinsonism in nonhuman primates and a rating scale that differentiated the two models. D(1) dopamine receptor agonists (SKF 81297, dihydrexidine) and D(2) dopamine receptor agonists [quinelorane, (+)-PHNO were administered to monkeys (Macaca fascicularis) displaying either mild parkinsonism (two doses of 0.6 mg/kg i.v. MPTP 1 month apart) or advanced parkinsonism (three doses of 0.6 mg/kg i.v. MPTP within 10 days). In normal monkeys (n = 3), SKF 81297 and dihydrexidine did not promote increased motor activity. In advanced parkinsonism (n = 4), D(1) and D(2) dopamine agonists effectively reversed the motor deficits. In contrast, the therapeutic benefits of D(1) agonists SKF 81297 and dihydrexidine were relatively limited in mild parkinsonism (n = 4). The D(2) agonists quinelorane and (+)-PHNO alleviated some symptoms in mild parkinsonism but also reduced balance and induced more dyskinesias than did D(1) agonists. Mild and advanced parkinsonism in nonhuman primates can be produced with fixed dosing regimens of MPTP. Based on the therapeutic efficacy and side effect profiles derived from these models, D(1) agonists are more promising for the treatment of advanced than of mild Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Behavior, Animal; Benzazepines; Dopamine Agents; Dopamine Agonists; Dyskinesia, Drug-Induced; Female; Macaca fascicularis; Male; Motor Activity; Motor Skills; Oxazines; Parkinsonian Disorders; Phenanthridines; Quinolines; Receptors, Dopamine D1