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Method of treatment of dopamine-related dysfunction

a dopamine receptor and dopamine-related technology, applied in the direction of aerosol delivery, drug composition, inorganic non-active ingredients, etc., can solve the problems of insufficient dopaminergic activity of parkinson's disease, eventual loss of efficacy, dyskinesia, etc., to prevent the induction of tolerance and high affinity

Inactive Publication Date: 2005-10-20
PURDUE RES FOUND & UNIV OF NORTH CAROLINA AT CHAPEL HILL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The patent text describes a method for treating disorders related to dopamine dysfunction, such as Parkinson's disease, using a full D1 agonist. This agonist has a short half-life and is administered in an intermittent dosing protocol to prevent tolerance and induce optimal dopamine receptor stimulation. The method is effective in treating patients with dopamine-related disorders and conditions involving peripheral dopamine receptors."

Problems solved by technology

Parkinson's disease involves the progressive degeneration of dopaminergic neurons, and, thus, Parkinson's disease results from insufficient dopaminergic activity.
The principal limitations of the long-term use of L-DOPA, however, include the development of unpredictable “on-off” phenomena, dyskinesias, psychiatric symptoms such as hallucinations, and eventual loss of efficacy.
Efforts to develop D1 agonists for the treatment of Parkinson's disease have met with limited success.
However, many full agonists have not evolved for clinical use either due to pharmacokinetic limitations or rapid development of tolerance (i.e., loss of therapeutic effects despite administration of the same or larger doses of drug).

Method used

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  • Method of treatment of dopamine-related dysfunction
  • Method of treatment of dopamine-related dysfunction
  • Method of treatment of dopamine-related dysfunction

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of 8,9-dihydroxy-1,2,3,11b-tetrahydrochromeno[4,3,2-de]isoquinoline Hydrobromide (Dinoxyline)

[0057] With reference to the following described experimental procedures, melting points were determined with a Thomas-Hoover melting point apparatus and are uncorrected. 1H NMR spectra were recorded with a Varian VXR 500S (500 MHZ) NMR instrument and chemical shifts were reported in values (ppm) relative to TMS. The IR spectra were recorded as KBr pellets or as a liquid film with a Perkin Elmer 1600 series FTIR spectrometer. Chemical ionization mass spectra (CIMS) were recorded on a Finnigan 4000 quadruple mass spectrometer. High resolution CI spectra were recorded using a Kratos MS50 spectrometer. Elemental analysis data were obtained from the microanalytical laboratory of Purdue University, West Lafayette, Ind. THF was distilled from benzophenone-sodium under nitrogen immediately before use and 1,2-Dichloroethane was distilled from phosphorous pentoxide before use.

1,2-Dimethox...

example 2

Additional Variations of the Subject D1 Agonists

1. Hexahydrobenzo[α]phenanthridines

[0070] Additional variations of hexahydrobenzo[α]phenanthridines are set forth with reference to Formula II and are synthesized as described in U.S. Pat. No. 5,420,134 incorporated herein by reference.

2. Dinapsoline

[0071] Additional variations of dinapsoline are shown in Table 1 as Compounds 1-47. The compounds in Table 1 are set forth with reference to Formula III and are synthesized as described in U.S. Pat. No. 5,959,110 incorporated herein by reference.

TABLE 1Cmpd.NumberRR1R2R3R4R5X1HHCH3HHHOH2HHHCH3HHOH3HHHHCH3HOH4HHC6H5HHHOH5CH3HCH3HHHOH6C3H7HHCH3HHOH7HHC2H5HHHOH8HHHC2H5HHOH9HHHCH3CH3HBr10C3H7HCH3CH3HHOH11C2H5HHCH3CH3HBr12CH3HHHC2H5HOH13C4H9HHOHHHOH14HHCH3OHHHOH15HHHFHHOH16HHOHHHHBr17HHBrHHHOH18HCH3HBrHHOCH319HCH3HHBrHOCH320HCH3CH3BrHHOCH321CH3HFHHHOH22CH3HHFHHOH23CH3HHHFHOH24C2H5HHOHHHF25C2H5HCH3OHHHF26C2H5HCH3OHCH3HF27C3H7HHCH3OHHCl28C3H7HHCH3CH3OHCl29C3H7HC2H5OHHHOH30C3H7HHHOHHOH31C4H...

example 3

Unilateral 6-OHDA Lesion Model for Parkinson's Disease

[0074] Summary. In the rat unilateral 6-hydroxydopamine (6-OHDA) rotation model of Parkinson's disease, 6-OHDA is infused unilaterally into the medial forebrain bundle, the substantia nigra, or the striatum. This treatment results in the destruction of dopamine terminals and neurons and a loss of striatal dopamine, and a profound functional dopaminergic supersensitivity develops on the lesioned side. When challenged with direct-acting dopamine receptor agonists, unilateral 6-OHDA rats turn contralaterally (away from the side of the lesion) because of the increased sensitivity of the postsynaptic dopamine receptors on the lesioned side. The experiments described below examine tolerance induced by the fall D1 agonist, dinapsoline, using the 6-OHDA model.

[0075] Subjects. Adult male Sprague-Dawley Rats (Hilltop Laboratories, Chatsworth, Calif.), weighing between 280 and 320 grams, were used as subjects. Animals were housed individu...

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Abstract

The present invention relates to the treatment of dopamine-related dysfunction using full D1 dopamine receptor agonists in an intermittent dosing protocol with a short, but essential, “off-period.” The D1 agonist concentration is reduced during the “off-period” to obtain a plasma concentration of agonist that suboptimally activates D1 dopamine receptors for a period of time to prevent induction of tolerance. Specifically, the method comprises the steps of periodically administering to a patient a full D1 agonist with a half-life of up to about 6 hours at a dose resulting in a first plasma concentration of agonist capable of activating D1 dopamine receptors to produce a therapeutic effect. The dose is reduced at least once every 24 hours to obtain a second lower plasma concentration of agonist that results in suboptimal activation of D1 dopamine receptors for a period of time sufficient to prevent induction of tolerance.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 60 / 261,889, filed Jan. 16, 2001 expressly incorporated by reference herein.FIELD OF THE INVENTION [0002] The present invention relates to the treatment of disorders resulting from dopamine-related dysfunction using full D1 dopamine receptor agonists. More particularly, the invention relates to using full D1 dopamine receptor agonists in an intermittent dosing protocol to treat disorders resulting from dopamine-related dysfunction. BACKGROUND AND SUMMARY OF THE INVENTION [0003] Dopamine is a neurotransmitter in the central nervous system that has been implicated in the etiology and treatment of several neurological and psychiatric disorders, such as schizophrenia, narcolepsy, restless leg syndrome, and Parkinson's disease, and of other disorders such as shock, including septic shock, congestive heart failure, arrhythmias, hypotension, and hypert...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D221/18A61K9/08A61K9/10A61K9/20A61K9/48A61K9/50A61K31/00A61K31/473A61K31/4741A61K45/00A61K45/06A61K47/02A61K47/12A61K47/22A61K47/24A61P1/08A61P9/02A61P9/04A61P9/06A61P9/12A61P15/10A61P25/00A61P25/14A61P25/16A61P25/18A61P25/28A61P43/00C07D491/06
CPCA61K31/00A61K45/06A61K31/4741A61K31/473A61P1/08A61P9/02A61P9/04A61P9/06A61P9/12A61P15/10A61P25/00A61P25/14A61P25/16A61P25/18A61P25/28A61P43/00
Inventor MAILMAN, RICHARD B.NICHOLS, DAVID E.HUANG, XUEMEI
Owner PURDUE RES FOUND & UNIV OF NORTH CAROLINA AT CHAPEL HILL
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