Modified Apomorphine Derivatives

McLean Hospital
posted on 05/18/2011

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Parkinson’s Disease is commonly treated with drugs which replace dopamine. The most common of these is L-DOPA, the immediate precursor of dopamine, but which has complications in clinical use, including development of rapid fluctuations in mobility (so-called “on-off” effect). Alternative treatments include drugs that directly mimic the actions of dopamine, including R(-)-apomorphine, a non-opioid, directly-acting dopamine agonist at both D1 and D2 receptors with no analgesic or addictive properties. Although R(-)-apomorphine therapy can yield sustained improvements in Parkinson’s patients whose treatment is accompanied by on-off motor changes, the drug is difficult to administer, poorly bioavailable by mouth, chemically unstable, and undergoes rapid metabolism to inactive metabolites. These inventions comprise novel chemical compounds designed for better specificity at the dopamine receptors and to overcome the problems encountered with apomorphine, particularly its lack of oral bioavailability and short half-life. The inventors have made specific modifications at certain positions of R(-)-apomorphine, designed to alter the molecule’s receptor binding properties, to create derivatives of the molecule with enhanced neuropharmacological properties. Molecular modifications have resulted in compounds having increased selectivity for the D2 receptor (higher potency at D2, lower at D1), or in being able to discriminate the high affinity and low affinity states of the D2 receptor, with correspondingly greater behavioral potency and duration of action with oral as well as systemic administration in animal models.
Potential Commercial Uses: The compounds of these inventions can be used for the treatment of Parkinson’s disease, sexual dysfunction (for which apomorphine can be transiently effective), and depressive disorders, and offer advantages over existing dopamine agonist compounds. The compounds described in the MCL 3817 application are fluorinated and can be used in PET or SPECT brain imaging.
Patent Status: McLean Hospital is the owner of U.S. Patent Number 7,648,995 and other pending U.S. patent applications claiming this invention. The research has been described in several published papers.
Licenses Available: McLean Hospital is offering a worldwide exclusive license to this technology.