Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-10-18
1999-09-28
Ford, John M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546 48, C07D22118, C07D491056
Patent
active
059591102
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention is directed to novel ligands for dopamine receptors. More particularly, the present invention is directed to optionally substituted pharmaceutical formulations for treatment of dopamine-related dysfunction of the central and peripheral nervous system.
BACKGROUND AND SUMMARY OF THE INVENTION
Dopamine, a neurotransmitter in the central nervous system, has been implicated in numerous neurological disorders. For example it has been hypothesized that excess stimulation of dopamine receptor subtypes may be linked to schizophrenia. Additionally, it is generally recognized that either excessive or insufficient functional dopaminergic activity in the central and/or peripheral nervous system may cause hypertension, narcolepsy, and other behavioral, neurological, physiological, and movement disorders including Parkinson's disease, a chronic, progressive disease characterized by an inability to control the voluntary motor system.
Dopamine receptors have traditionally been classified into one of two families (D.sub.1 and D.sub.2) based on pharmacological and functional evidence. D.sub.1 receptors preferentially recognize the phenyltetrahydrobenzazepines and lead to stimulation of the enzyme adenylate cyclase, whereas D.sub.2 receptors recognize the butyrophenones and benzamides and are coupled negatively (or not at all) to adenylate cyclase. It is now known that several subtypes of dopamine receptors exist and at least five genes code for subtypes of dopamine receptors: D.sub.1, D.sub.2, D.sub.3, D.sub.4 and D.sub.5. The traditional classification, however, remains useful, with the D.sub.1 -like class comprising the D.sub.1 (D.sub.1A) and the D.sub.5 (D.sub.1B) receptors, whereas the D.sub.2 -like class consists of the D.sub.2, D.sub.3 and D.sub.4 receptors.
Central nervous system drugs exhibiting affinity for the dopamine receptors are generally classified not only by their receptor selectivity, but further by their agonist (receptor stimulating) or antagonist (receptor blocking) activity. While the physiological activities associated with the interaction of dopamine with the various receptor subtypes are not fully understood, it is known that ligands exhibiting selectivity for a particular receptor subtype will produce more or less predicable neuropharmaceutical results. The availability of selective dopamine receptor antagonist and agonist compounds will enable the design of experiments to enhance understanding of the manifold functional roles of D.sub.1 receptors and lead to new treatments for various central and peripheral nervous system disorders.
Initially, studies of dopamine receptors were focused on the D.sub.2 family, however the critical role of the dopamine D.sub.1 receptor in nervous system function has recently become apparent. Early work on selective D.sub.1 receptor ligands primarily focused on molecules from a single chemical class, the phenyltetrahydrobenzazepines, such as the antagonist SCH23390 (1): ##STR2## Several of the phenyltetrahydrobenzazepines were found to be D.sub.1 receptor agonists; however, the agonists derived from this class efficacy. Even SKF82958, purported to be a full agonist, recently has been shown not to have full intrinsic efficacy in preparations with decreased receptor reserve. The differentiation between agonists of full and partial efficacy is important to the medical research community due to the difference in the effect these compounds have on complex central nervous system mediated events. For example, dihydrexidine and the full agonist, A-77636, have exceptional anti-parkinsonian effects in the MPTP-treated monkey model, whereas partial agonists are without significant activity. More recent data suggest that full and partial agonists also differ in their effects on other complex neural functions.
Accordingly, researchers have directed their efforts to design ligands that are full agonists, having full intrinsic efficacy. One such compound is ##STR3## The structure of dihydrexidine (3) is unique from other D.sub.1 agonists beca
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Ghosh Debasis
Mailman Richard
Nichols David E.
Ford John M.
Purdue Research Foundation
University of North Carolina
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