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. doi: 10.1007/s00213-011-2625-5. Epub 2012 Jan 6.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Area Under Curve
  • Disease Models, Animal
  • Dopamine Agonists / administration & dosage
  • Dopamine Agonists / pharmacokinetics
  • Dopamine Agonists / pharmacology*
  • Dose-Response Relationship, Drug
  • Injections, Intraperitoneal
  • Male
  • Motor Activity / drug effects
  • Parkinsonian Disorders / drug therapy*
  • Parkinsonian Disorders / physiopathology
  • Phenanthridines / administration & dosage
  • Phenanthridines / pharmacokinetics
  • Phenanthridines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D1 / drug effects*
  • Receptors, Dopamine D1 / metabolism

Substances

  • 2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno(3,4-c)isoquinoline
  • Dopamine Agonists
  • Phenanthridines
  • Receptors, Dopamine D1
  • dihydrexidine