Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1995-06-07
1998-11-24
Low, Christopher S. F.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 245, 536 243, 536 2431, 536 2433, 536325, 536352, 536353, 536366, 435 6, 4351723, 4353201, 435375, 424417, 424450, 935 6, 935 8, 935 34, 935 76, A01N 4304, C07H 2104
Patent
active
058407081
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to treatment of pathological conditions associated with abnormalities in dopamine receptors. In particular, it relates to diagnosis and treatment of patients having such pathological conditions by administration of oligonucleotides antisense to one or more mRNA molecules encoding one of the several dopamine receptors.
BACKGROUND OF THE INVENTION
Abnormal activity of the dopaminergic nervous system has been implicated in a number of motor and behavioral disorders including Parkinson's disease, Huntington's disease, tardive dyskinesia, certain forms of schizophrenia and other dystonias and dyskinesias. Dysfunctions of the dopaminergic system may be caused either by a reduced or increased activity of the dopaminergic system or by the inability of the systems to be modulated by a changing external or internal environment.
Dopamine is one of the major catecholamine neurotransmitters in the mammalian brain. Dopamine exerts its effect in part by binding to G protein-coupled dopamine receptors. Pharmacological and molecular biological studies have shown that the dopamine receptor has at least five subtypes, designated D.sub.1-5. The best characterized of these are D.sub.1 and D.sub.2. The D.sub.2 subtype exists in a long and short form, the long form having a larger intracellular loop than the short form. These receptor subtypes appear to be anatomically, biochemically and behaviorally distinct. For example, D.sub.1 and D.sub.2 receptors have different anatomical distributions, in that only D.sub.1 receptors are found in the retina and only D.sub.2 receptors are found in the pituitary, but both D.sub.1 and D.sub.2 are found in the striatum and substantia nigra. D.sub.1 and D.sub.2 receptors are reported to have opposite biochemical effects on adenylate cyclase activity, and stimulation of D.sub.1 and D.sub.2 receptors produces different behavioral responses. See Weiss et al., Neurochemical Pharmacology--A Tribute to B. B. Brody, E. Costa, ed.; Raven Press, Ltd., New York; pp. 149-164 (1989).
Recently, three new subtypes of dopamine receptors have been discovered. On the basis of nucleotide and amino acid sequence homology, D.sub.3 and D.sub.4 have been found to be related to D.sub.2, and D.sub.5 is related to D.sub.1. Hence, the dopamine receptor subtypes may be categorized into two subfamilies, D.sub.1 and D.sub.5 being members of the D.sub.1 subfamily, and D.sub.2, D.sub.3 and D.sub.4 being members of the D.sub.2 subfamily. See Sibley et al., Trends in Pharmacological Sciences, 13: 61-69 (February, 1992).
The dopamine receptor subtypes can be separately and independently modulated through the administration of selective agonists and antagonists. For example, whereas dopamine and apomorphine are agonists of both D.sub.1 and D.sub.2 receptors, SKF 38393 (Setler et al., Eur. J. Pharmacol., 50: 419-30, 1978) is a selective agonist of only D.sub.1 and quinpirole (Tsuruta et al., Nature, 292: 463-65, 1981) is a relatively selective agonist for the D.sub.2 receptor. It should be emphasized, however, that the currently available dopaminergic drugs have only a relative selectivity for the various dopamine receptors. Indeed, there are recent reports suggesting that quinpirole may have a higher affinity for D.sub.3 receptors than for D.sub.2 receptors (see Sokoloff et al., Nature, 347: 146-151 (1990)).
It is not surprising, therefore, that the use of specific and nonspecific neuroleptic drugs in the treatment of dopaminergic disorders is contraindicated by the fact that such drugs often produce numerous side effects, presumably due to cross-reactivity with other dopamine receptor subtypes, or even with other classes of neuroreceptors. For example, the therapeutic action of many neuroleptic drugs appears to be due to a blockade of dopamine D.sub.2 receptors. However, patients treated with such drugs often develop tardive dyskinesia, possibly because of the up-regulation of dopamine receptors. A further example is that benzazepines (such as SKF-38393), which are a major D.sub
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Allegheny University of the Health Sciences
Low Christopher S. F.
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