Purdue Research Foundation

The University of North Carolina at Chapel Hill

Other

Richard B Mailman

David E Nichols

Debasis Ghosh

Russell A Grubbs

Xuemei Huang

Novel dopamine receptor ligands of the formula:pharmaceutical formulations of such compounds, and a method using such compounds for treating a patient suffering from dopamine-related dysfunction of the central or peripheral nervous system, are described. The compounds are expected to be useful in treating Parkinson's disease, improving cognition, improving memory, improving the negative symptoms of schizophrenia, improving attention-deficit hyperactivity disorder and related developmental disorders, treating substance abuse disorders, and in treating various peripheral conditions where changes in dopamine receptor occupation affects physiological function, including organ perfusion, cardiovascular function, and selected endocrine and immune system functions.

Chromeno[4,3,2-de]isoquinolines as potent dopamine receptor ligands

The present invention relates to the treatment of dopamine-related dysfunction using full Ddopamine receptor agonists in an intermittent dosing protocol with a short, but essential, 'off-period.' The Dagonist concentration is reduced during the 'off-period' to obtain a plasma concentration of agonist that suboptimally activates Ddopamine 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 Dagonist with a half-life of up to about 6 hours at a dose resulting in a first plasma concentration of agonist capable of activating Ddopamine 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 Ddopamine receptors for a period of time sufficient to prevent induction of tolerance.

Method of treatment of dopamine-related dysfunction

Chromeno&lsqb;4,3,2-DE&rsqb;isoquinolines as potent dopamine receptor ligands

The present invention is directed to a novel dopamine receptor ligands of the formula:

Fused isoquinolines as dopamine receptor ligands

Trans-hexahydrobenzo[a]phenanthridine of the formula ##STR1## wherein R is hydrogen or C.sub.1 -C.sub.4 alkyl; R.sub.1 is hydrogen or a phenoxy protecting group, X is fluoro, chloro, bromo, iodo or a group of the formula--OR.sub.5, and R.sub.2, R.sub.3, and R.sub.4 are independently selected from the group consisting of hydrogen, C.sub.1 -C.sub.4 alkyl, phenyl, fluoro, chloro, bromo, iodo, or a group --OR.sub.1 provided that at least one of R.sub.2, R.sub.3, and R.sub.4 are other than hydrogen, are novel ligands for dopamine receptors.

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Chapel Hill, NC, United States of America

Richard B Mailman