Dopamine is an ubiquitous neurotransmitter found in the central nervous system (CNS) as well as in the peripheral nervous system of mammals. In the CNS, it is involved with motor function, perception, cognition, attention, arousal, motivation and emotion. In the peripheral nervous system, it is involved, for example, in the control of blood to the kidneys and in autonomic ganglion transmission.
It is now generally recognized that dopamine receptors in the CNS exist as five different receptors, designated as D1 through D5. Additionally, they are further classified as to whether they fall into the D1-like or D2-like family of receptors based upon their pharmacological differences. Accordingly, D1 and D5 are considered part of the D1 family of receptors, whereas D2, D3 and D4 are considered part of the D2 family.
Dopamine imbalance is believed to play a key role in a number of CNS-related disorders such as schizophrenia, Parkinson's disease, drug abuse, eating disorders and depression.
D1 receptors are positively linked to adenylate cyclase and are found in all areas of the human brain, with the frontal cortex and the substantia nigra pars compact a particularly rich with D1 receptors. D1 receptors are also found in the periphery, and have been identified in kidney and heart tissue. As such, disease states attributed to aberrations of the dopamine neuronal network could possibly be treated by drugs, which are selective for the D1 receptor. And, of particular interest are a class of drugs that would act as selective agonists at D1 receptors.
For instance D1 selective agonists have shown utility in treating Parkinson's disease. The loss of striatal dopamine within the basal ganglia, the region of the mammalian brain that is involved with motor control, has been established as the fundamental deficit in Parkinson's disease and primary to the etiology of that disease state. This deficiency is addressed via dopamine replacement therapy, primarily with L-DOPA (3,4-dihydroxyphenylalanine), which is converted to dopamine within the brain. Other compounds that act as agonists at the dopamine receptor have also been used to treat Parkinson's disease. Bromocriptine, the most widely used direct-acting dopamine agonist for the treatment of Parkinson's disease, is often administered with L-DOPA in order to lower dosages of the latter required to achieve the desired therapeutic response. Bromocriptine alone has been shown to relieve Parkinson's disease symptoms in some early Parkinson's disease patients, allowing for a delay in the onset of L-DOPA therapy. Chronic L-DOPA use is associated with a number of serious side effects and limitations, such as the development of dyskinesias, severe response fluctuations (on-off phenomenon) and diminishing efficacy during treatment.
Anti-schizophrenic drugs are postulated to exert their effects by blocking the dopamine receptors (i.e., acting as receptor antagonists), and consequently preventing excess receptor stimulation (G. P. Reynolds, TIPS, 13:116-121, 1992). However, these antipsychotic agents frequently produce undesirable side effects, the most common of which are the extrapyramidal effects that include bizarre involuntary movements and Parkinson-like states, as well as sedation and hypotension. Because of these often-severe side effects and the high incidence of patients unresponsive to dopamine blocking drugs, novel and improved therapies continue to be sought.
One complement to dopamine receptor antagonists for the treatment of schizophrenia has included the use of low doses of dopamine agonists, such as apomorphine and bromocriptine, which have been reported to produce antipsychotic effects, possibly due to preferential activation of dopamine presynaptic receptors resulting in decreased dopaminergic activity (M. Del Zompo et al, Progress in Brain Research, 65:41-48, 1986 and H. Y. Meltzer, Drug Development Research, 9:23-40, 1986). In addition, the dopamine D1-selective agonist, SKF 38393, when used in conjunction with the antipsychotic drug, haloperidol, a D2 antagonist, has been shown to ameliorate the undesired side effects of the haloperidol (M. Davidson et al., Arch Gen. Psychiatry, 47:190-191, 1990).
There is evidence that dopamine plays a role in the brain reward system. For example, animals trained to self-administer cocaine will increase their consumption of this drug after treatment with either a D1 or a D2 receptor antagonist, presumably in order to maintain the elevated dopamine levels responsible for the drug's euphorigenic and reinforcing properties (D. R. Britton et al, Pharmacology Biochemistry & Behavior, 39:911-915, 1991). The D1 agonist, SKF 38393, has also been reported to decrease food intake by rats, presumably by direct action of the drug on neural feeding mechanisms. Because of this interrelationship between dopamine and reward, dopaminergic agents would be useful for the treatment of substance abuse and other addictive behavior disorders, including cocaine addiction (A. L. Chausmer et al. Psychopharmacology, 159:145-153, 2002) nicotine addiction and eating disorders.
Affective disorders, the most common psychiatric disorders in adults, are characterized by changes in mood as the primary clinical manifestation, and result from a reduction in the central nervous system of certain biogenic amine neurotransmitters, such as dopamine, noradrenaline and serotonin. Currently available antidepressants work primarily by raising biogenic amine neurotransmitter levels, either by inhibiting their uptake or preventing their metabolism. No antidepressant drug to date, however, can substitute for electroconvulsive shock therapy for the treatment of severe, suicidal depression. Currently available drugs for treating affective disorders unfortunately suffer from delayed onset of action, poor efficacy, anticholinergic effects at therapeutic doses, cardiotoxicity, convulsions and the possibility of overdosing. A large number of clinically depressed individuals remain refractory to currently available therapies. A role for direct-acting dopamine agonists in antidepressant therapy has been suggested based on the effects observed for several dopamine agonists in various animal models (R. Muscat et al., Biological Psychiatry, 31:937-946, 1992).
A role for dopamine has also been established in cognition and attention mechanisms. Animal studies support the role of dopamine in attention-related behaviors involving search and exploratory activity, distractibility, response rate, discriminability and the switching of attention. Treatment of cognitive impairment and attention deficit disorders via dopamine-based therapy has been proposed and is under active investigation (A. Nieoullon, Progress in Neurobiology, 67:53-58 (2002) and T. Sawaguchi and P. S. Goldman-Rakic, Science, 252:947-940 (1991); and P. S. Goldman-Rakic et al., Science, 287:2020-2022 (2000)).
In addition, dopamine has been identified with a number of effects in the periphery, and has been used in the treatment of shock, congestive heart failure and acute renal failure. Stimulation of the peripheral D1 receptors causes vasodilation, particularly in the renal and mesenteric vascular beds where large numbers of these receptors are found. The utility of dopamine has been limited, however, by its ability to cause vasoconstriction at higher concentrations, presumably due to its secondary effects on adrenergic receptors, and by its emetic effects due to peripheral D2 stimulation. Agents selective for the peripheral D1 receptors appear to offer significant advantages over treatments used currently for these and other related disorders (M. F. Lokhandwala, Drug Development Research, 113:123-124 (1987)).
Certain compounds within the scope of the present invention are generically disclosed and claimed in U.S. Pat. No. 6,004,982, the entire disclosure of which is herein incorporated by reference. For example, certain (4-piperidinyl)-1H-2-benzopyrans) were disclosed therein to be useful as antipsychotics. The present invention represents single enatiomers of piperidinylisochromans as dopamine agonists.