Method of treatment of dopamine-related dysfunction

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...

AI Technical Summary

Benefits of technology

[0006] This hypothesis is supported by recent studies showing that several D1 receptor full agonists are efficacious in non-human primate Parkinson's disease models and in humans with Parkinson's disease. Accordingly, researchers have directed their efforts to design ligands that are full agonists (i.e., have full intrinsic efficacy) for the D1 receptor. One such compound is dihydrexidine, a hexahydrobenzo[α]phenanthridine of the formula: The structure of dihydrexidine is unique from other D1 agonists because the accessory ring system is tethered, making the molecule relatively rigid. The dihydrexidine-based model has served as the basis for the design of additional D1 receptor agonists. The design and synthesis of D1 receptor agonists having high intrinsic activity is important to the medical research community due to the potential use of full agonists to treat complex central nervous system mediated events, and also conditions in which peripheral dopamine receptors are involved.

[0008] The present invention provides a method of treating disorders resulting from dopamine-related dysfunction, such as Parkinson's disease, by using a full D1 dopamine receptor agonist in an intermittent dosing protocol. According to this protocol, the plasma concentration of the D1 agonist is reduced to a concentration below the level required for optimal dopamine receptor stimulation (e.g., the concentration of the D1 agonist at the D1 receptor can be decreased to a level such that receptor occupation is negligible (<5% high affinity)) for a time sufficient (i.e., at least one hour per each 24 hour period) to prevent the induction of tolerance. This dosing protocol is useful for treating patients having a dopamine-related dysfunction of the central nervous system (as evidenced by an apparent neurological, psychological, physiological, or behavioral disorder), as well as conditions in which peripheral dopamine receptors are involved (including target tissues such as the kidney, lung, endocrine, and cardiovascular systems).

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).

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