Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1997-06-03
2001-12-04
Kunz, Gary L. (Department: 1647)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007200, C435S007210
Reexamination Certificate
active
06326156
ABSTRACT:
The present invention relates to a screening method comprised of testing an LC132 receptor agonist in screening assays for neurological and/or psychiatric disorders. More specifically, the screening method is based on bringing an LC132 receptor in contact with an agent suspected of acting as an agonist of LC132 receptor function followed by the detection of the binding and/or the agonist activity of the compound and then the testing of an agent with LC132 agonist activity in an antiepileptic, anticonvulsant and/or anxiolytic screening test to demonstrate therapeutically relevant activity in these disorders.
At present, benzodiazepine receptor agonists (e.g., alprazolam, diazepam, lorazepam) still represent the predominant treatment in clinical medicine for anxiety disorders, especially acute anxiety. Since benzodiazepine receptor agonists have anticonvulsant properties, some are also used as antiepileptic drugs. More recently, other drug classes have found clinical use in the treatment of anxiety disorders, for example selective serotonin reuptake inhibitors (e.g., fluoxetine) and buspirone. Treatment of epilepsies is currently dominated by drugs such as carbamazepine, phenytoin, valproate, ethosuximide, and phenobarbital. As discussed below, the available drugs used in the pharmacological treatment of anxiety, epilepsies, and convulsions are not optimal.
Anxiety is a physiologic phenomenon that acts as a warning signal for a real or potential danger. Anxiety becomes pathologic when it occurs in the absence of any real danger or when the intensity of the emotion is exaggerated. Both physiologic and pathologic anxiety can be life-threatening when occurring in the face of pre-existing organic disorders and may create or perpetuate various physiologic dysfunctions. The diverse anxiety disorders represent relatively common psychiatric disorders with an estimated combined prevalence within the general population of about 4-8 percent. The immediate relief provided by benzodiazepine receptor agonists in treating anxiety disorders is well documented. Although the efficacy of these drugs appears to be maintained over a long period, a series of issues arise when treatment is administered for more than several weeks. Although undesirable side-effects can largely be avoided by optimising dosage of benzodiazepine receptor agonists for the individual patient, doses required for severe cases of anxiety and epilepsies as well as for reducing pathologic muscle tone frequently depress vigilance to a level that disturbs intellectual function and reduces attention and precision for various skills (operation of machines, car driving). The individual sensitivity to this oversedation varies greatly. Muscle relaxation may result in blurred speech and disturbed gait, especially in elderly patients. Behavioral disinhibition may occur at higher doses and even at normal doses in individuals having minimal experience with centrally active drugs. Problems can also occur due to long-lasting exposure to benzodiazepine receptor agonists. One such is the development of tolerance to a therapeutic effect. Loss of antiepileptic efficacy occurs in a fair proportion of patients (manifested as escape phenomena). Physical dependence manifested as drug discontinuation symptoms following abrupt withdrawal is a function of duration of drug exposure, dose, duration of action of the drug, and the personality of patients. In marked contrast to anxiolytics acting via benzodiazepine receptor agonism (which exhibit anticonvulsant, muscle relaxant, and sedative/hypnotic effects), the azaspirodecanedione buspirone presents only anxiolytic activity. It has been hypothesized that the mechanism of action of buspirone involves partial agonism at the serotonin1A receptor. Advantages of buspirone include less sedation, less psychomotor impairment in conjunction with ethanol consumption, reduced physical dependence, and a much lower abuse liability than for benzodiazepine receptor full agonists. However, the long latency in the onset of anxiolytic activity is a pronounced difference to classic benzodiazepine tranquilizers which act rapidly. In addition, there are possible problems in treatment compliance for buspirone and questions about efficacy in patients previously treated with benzodiazepine receptor agonists or exhibiting severe anxiety. Buspirone is not only a valuable addition to the medical armamentarium whose place is gradually becoming more clearly defined, but also very important from the theoretical standpoint insofar as it is the first anxiolytic to meet the rigorous clinical efficacy and safety standards of modern. In view of the mechanism of action of selective serotonin reuptake inhibitors (SSRIs), it appears that the resulting increased availability of the neurotransmitter serotonin within the synaptic cleft is responsible for the pharmacological effects of this drug class. However, onset of the therapeutic action of SSRIs is slow, usually requiring at least several weeks. Although originally developed and predominantly used as antidepressants, SSRIs have been increasingly used in treating panic disorder, e.g. fluoxetine or obsessive-compulsive disorder, e.g. fluvoxamine. SSRIs are generally well tolerated, nonetheless, common adverse effects for compounds in this class include nervousness, tremor, dizziness, headache, insomnia, sexual dysfunction, nausea, and diarrhea. In addition, the tricyclic antidepressant clomipramine, which is a potent nonselective serotonin reuptake inhibitor, is approved for treatment of obsessive compulsive disorder [e.g. see: Martin and Haefely, in “Principles of Pharmacology, Eds. Munson et al., Chapman & Hall, N.Y., 1995, pp. 243-277].
Epilepsy is a neurologic disorder which affects up to about 1 percent of the population. This chronic condition is characterised by recurrent spontaneous seizures not caused by active cerebral disease. Seizures are sudden, involuntary, time-limited alterations in behavior associated with excessive discharges of cerebral neurons. Today the epilepsies are usually classified according to the main seizure type presented by the patient (a given patient may have more than one seizure type but one is usually more frequent than the others and is used as basis for classification). A practical advantage of the classification by seizure type is that it allows, to a certain degree, prediction of responsiveness to therapeutic alternatives. Generally, only about half of the patients will have their seizures satisfactorily controlled with antiepileptic drugs; the remaining half will be divided into patients having occasional seizures and patients who have uncontrolled seizures and/or unacceptable adverse effects from antiepileptic medications. Furthermore, the drugs currently used frequently cause side effects. There are multiple etiologies for seizures and the origin often remains obscure, thus, antiepileptics as well as other drugs exhibiting anticonvulsant effects are important therapeutically. (e.g. see: Lloyd and Gillenwater, in “Principles of Pharmacology, Eds. Munson et al., Chapman & Hall, N.Y., 1995, pp. 363-398).
Previously, a seventeen amino-acid-long peptide (F-G-G-F-T-G-A-R-K-S-A-R-K-L-A-N-Q) (SEQ ID NO: 1) called orphanin FQ or nociceptin has been isolated from rat brain (Meunier et al., Nature 377: 532-535, 1995) and from porcine hypothalami (Reinscheid et al., Science 270: 792-794, 1995). The amino acid sequence of orphanin FQ is identical with that of nociceptin and will be thereafter referred to as OFQ. Julius (Nature 377: 476, 1995) discusses the OFQ discovery noting that this peptide shares greatest sequence similarity with dynorphin A, one of five established endogenous ligands for opioid receptors. OFQ inhibits adenylate cyclase in CHO(LC132
+
) cells in culture and induces hyperalgesia when administered intracerebroventricularly to mice (Meunier et al., loc. cit.). The pattern of results indicate that this heptadecapeptide is an endogenous agonist of the LC132 receptor and it appears to have pro-nociceptive properties. Reinscheid et
Civelli Olivier
Martin James Richard
Monsma Frederick
Moreau Jean-Luc
Nothacker Hans-Peter
Dubberley F. Aaron
Gucker Stephen
Hoffmann-La Roche Inc.
Johston George W.
Kunz Gary L.
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