Recent Patents on CNS Drug Discovery (Discontinued) - Volume 3, Issue 2, 2008

A compelling case for the potential utility of vasopressin (AVP) antagonists as a novel therapeutic class for the treatment of stress-related affective illness has emerged based on observations in depressed individuals, findings in animal models of anxiety and depression, and an understanding of changes in hypothalamic-pituitary-adrenal (HPA) axis regulation under chronic stress. The scientific bases for vasopressin antagonists as a pharmacotherapy for anxiety and depression include: 1) the neuroadaptation and dysregulation of HPA function that accompanies chronic stress in affected humans and in animal models of anxiety and depression, 2) recognition that AVP, not corticotrophin releasing factor (CRF), drives HPA function associated with chronic psychological stress, 3) the CNS localization of vasopressin V1a and V1b receptors in limbic system regions involved in HPA regulation and control of social behaviors, and 4) preclinical data showing efficacy in animal models employed as screens for anxiolytic and antidepressant activity. The public health need for new pharmaceutical treatments for stress-related affective illness is well documented. In the United States alone, anxiety and depression affect some 40 million people each year and carry a conservatively estimated annual total economic burden of at least $125 billion. Existing pharmacotherapies for both indications are not uniformly effective and frequently have undesirable side effects. These limitations demonstrate that a new treatment approach through vasopressin receptor antagonism in the CNS may offer significant opportunities for improved outcomes. In this review, the development of compounds in this class since 2005 is considered. The most advanced clinical candidates and newer compounds described in recent patents are presented.

The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells have been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. Acetylcholine, in fact is synthesized not only in the nervous system but also in other tissues where its local action contributes to the modulation of various cell functions (e.g. survival, proliferation). The possible involvement of acetylcholine and muscarinic receptors in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer and Sjogren's diseases). This review will focus on the potential implications of muscarinic receptors in tumour progression and in nociception and the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin,; patent, US5096890; US6106864 ) have also been demonstrated to arrest tumour progression in nude mice. Moreover muscarinic agonists such as vedaclidine, CMI- 936 and CMI-1145 have been demonstrated to have analgesic effects, in animal models comparable or more pronounced to those produced by morphine or opiates.

Several recent studies from the author's laboratory have shown that tamoxifen, at higher concentrations than used for breast cancer and given i.v., can substantially prevent tissue infarct and behavioral deficits in reversible and permanent rat focal stroke models for up to at least 14 days after initiation of ischemia. Longer times and purely i.p. or oral administration have not yet been tried. Its marked effectiveness may be because it has several neuroprotective modes of action including free radical scavenging and, being highly lipid soluble, readily crosses the blood-brain barrier. Plus, it has a three hour therapeutic window. Thus it meets many of the STAIR criteria and should be a promising candidate for clinical use. However, a number of its positive effects were exhibited by the free radical trapping agent NXY-058, which also functions as a free radical scavenger. In two recently completed clinical trials (SAINT 1 and 2) NXY-058 had marginal positive effects and did not meet treatment criteria, respectively. Differences that may make tamoxifen still desirable and the problem of predicting clinical efficacy from successful animal studies are discussed.

Over the past decade, a tremendous amount of consistent data have accumulated showing reduced levels of the 42 amino acid isoform of amyloid-β (Aβ42) in cerebrospinal fluid (CSF) from patients with mature as well as incipient Alzheimer's disease (AD). However, as CSF analyses necessitate a spinal tap, which some consider hard to implement in the clinical routine and in clinical trials, there is a strong interest in the possible association of Aβ levels in plasma with AD. This review provides an update on the current status of research on plasma Aβ as a biomarker for AD in the context of recent patents in the field.

Brain ischemia induces the IGF-1 system in damaged regions, and exogenous administration of IGF-1 after injury is neuroprotective and improves long-term neurological function. The short treatment window can be extended by mild hypothermia, probably due to delayed apoptosis. Nevertheless, the poor central uptake of IGF-1 and its mitogenic potential preclude clinical application. The N-terminal tripeptide of IGF-1 (glycine-proline-glutamate, GPE) is neuroprotective after central administration. Central uptake of GPE is injury dependent, and it is rapidly degraded in the plasma. Intravenous infusion of GPE prevents brain injury and improves long-term functional recovery, with a broad effective dose range and a 3-7 hour therapeutic window. GPE does not interact with IGF receptors. G-2meth-PE, a GPE analogue with improved stability, has a prolonged plasma half life and is neuroprotective after ischemic injury. Neuroprotection by GPE and its analogue may involve modulating inflammation, promoting astrocytosis and inhibiting apoptosis, and the analogue may have a vascular effect. Cyclo-glycyl-proline (cGP) is an endogenous diketopiperazine possibly derived from GPE. Cyclic GP and its analogue cyclo-L-glycyl-L-2-allylproline (cG-2allylP) are neuroprotective after ischemic injury. cG-2allylP crosses the BBB independent of injury and remains detectable several hours after a single administration. Repeated peripheral administration of cG-2allyP improves somatosensory-motor function and long-term histological outcome.

Current epilepsy therapy is symptomatic using antiepileptic drugs. This therapy suppresses seizures but does not prevent or cure epilepsy. Treatment strategies that could interfere with the process leading to epilepsy (epileptogenesis) would have significant benefits over the current approach. Neuronal damage contributing to restructuralization of the neuronal networks (especially in the hippocampus during temporal lobe epilepsy) is one of the significant components of ongoing epileptogenesis. Thus, treatment strategies alleviating seizure induced neuronal damage may become significant players against the deteriorating process of epileptogenesis. Current antiepileptic drugs, especially valproic acid, have some neuroprotective potential. However, frequently this potential is either insufficient or the side effects of long-term therapy cancel out the benefits. The attention is therefore aimed at different classes of drugs with already established neuroprotective potential. Steroid hormones are under investigation, especially two groups of these compounds: β-estradiol and the selective estrogen receptor modulators - SERM. In low doses, β-estradiol has neuroprotective potency in neurodegenerative diseases. However, its use in seizure-induced neuroprotection is confounded by the common perception of proconvulsant features of estrogens. Here, we review that both proconvulsant and neuroprotective features apply only under specific conditions and may be separated by therapy taking into account the dosage paradigm, timing, sex of the subjects and their gonadal hormone status. Several studies have demonstrated that β- estradiol has indeed potency to protect neurons from seizure-induced damage. Additional studies are required to further elucidate the effects, exact conditions, and especially mechanisms of action of β-estradiol in seizure-induced neuroprotection since new specific SERM may help to avoid some undesirable effects.

The effect of dexamethasone (DEX) and its interaction with morphine has been studied on transmurallystimulated guinea-pig ileum preparation, gastrointestinal transit and analgesia. Transmurally-stimulated guinea-pig ileum preparation: DEX dose-dependently reduced the contractions of the ileum. Proteic synthesis inhibitors did not modify the inhibition induced by DEX whereas RU-38486, a glucocorticoid antagonist receptor, antagonized completely the inhibitory effect of DEX. Gastrointestinal transit: DEX was found to antagonize morphine-, atropine- and verapamil-induced constipation. Cycloheximide does not modify the DEX effects. RU-38486 reverses both the inhibitory action of DEX on gastrointestinal transit and its reducing effect on morphine-induced constipation. Analgesia: DEX reduced the antinociception induced by mu agonists, morphine, DAMGO and beta endorphin whereas the steroid exerted little or no influence on the antinociception induced by a delta1 agonist, DPDPE and delta2 agonist deltorphin II. DEX potentiated the antinociception induced by the K agonist, U50,488. Cycloheximide, a protein synthesis inhibitor, prevented the antagonism by DEX of responses to the mu opioid agonists. Finally, i.c.v. injection of DEX significantly reduced morphine analgesia in Swiss mice whereas no effects were observed in DBA/2J and C57BL/6 mice. In addition, i.p. injection of DEX significantly reduced morphine analgesia in all three strains. Our data indicate that in the rodent brain there is an important functional interaction between the corticosteroid and the opioid systems at least at the mu. receptor level, while delta and K receptors are modulated in different ways. These results, particularly the effects of drug interaction for i.c.v. administration, strongly confirm a central site for DEX and RU 38486 action as well as the use of different genetic strains may provide a useful approach for studying DEXmorphine analgesia interaction.

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