Recent Patents on CNS Drug Discovery (Discontinued) - Volume 1, Issue 2, 2006

The brain continues to remain an area where little corrective surgery can be performed. Recently, the ability to reverse some brain damage and perhaps prevent further damage has moved closer to hospitals and clinics. Several agents demonstrating neuroprotective properties and even neural regeneration have been developed to the extent that they have been granted patent protection, one of the first steps in commercial development. The concept of neuroprotection is the administration of an agent that can reverse some of the damage or prevent further damage. Some agents offer protection against cell degeneration due to oxidative stress whilst other agents specifically protect against neural stroke damage. In the early years of neuroprotective research, most compounds were not designed as such but were found to possess neuroprotective activity in later studies. However, the original structures have since become the leads for purely synthetic derivatives. Most of the agents are or were designed from biologically active natural products, either plant extracts or endogenous peptides/proteins and even sequences of RNA. This review will present the most recently patented neuroprotective agents.

Activity of protein kinase C (PKC) isozymes plays a critical role in various types of learning and memory. In addition, abnormal functions of PKC signal cascades in neurons represent one of the earliest changes in the brains of patients with Alzheimer's disease (AD) and dementia related to ischemic/stroke events. In preclinical studies, inhibition or impairment of PKC activity leads to compromised learning and memory, whereas an appropriate activation of PKC isozymes has been found to enhance learning and memory and/or to produce antidementic effects. The PKC activators not only increase activity of PKC isozymes and thereby restore PKC signaling activity but also reduce the accumulation of neurotoxic amyloid and tau protein hyperphosphorylation in the brain. These observations strongly suggest that PKC pharmacology may represent an attractive area for the development of cognitive therapeutics and agents against dementia in the future.

The blood-brain barrier (BBB) serves to protect the central nervous system (CNS) from damage by exogenous molecules. In doing so, it also can prevent some drugs from reaching their sites of action. Accordingly, a variety of methods for bypassing the BBB have been developed. Ekwuribe et al. recently patented a method for drug conjugation in order to increase lipophilicity, and therefore BBB permeability. Shalev developed a device for opening the barrier via parasympathetic nerve fiber stimulation and Gudkov et al. produced compounds that modulate the activity of multidrug transporter proteins, by either increasing or decreasing the selective permeability of the BBB. A variety of CNS disorders contribute to barrier disruption, and detection of this opening can be used for both diagnostic purposes and for determining time periods when drugs can more easily enter the CNS. While expensive and time-consuming imaging techniques are currently used for this purpose, Janigro et al. have devised a method for detecting plasma levels of S100b, a peripheral protein marker for BBB disruption. These techniques for both "reading" and "writing" the BBB will help new and old medications to reach their pharmacological targets in the CNS.

Alcohol use disorders represent a substantial public health problem all over the world affecting approximately 2 billion alcohol users worldwide as estimated by the WHO in 2000. Given the harmful effects of alcohol on the distressed individuals and society as a whole, there is an increasing urge for the development of new, more efficient medications. Although, investigation of the mechanisms underlying the actions of ethanol in the central nervous system has been ongoing for more than a century, the exact mechanism by which ethanol exerts its effect is still a matter of debate. In recent years, scientists discovered evidence that alcohol acts on several neurotransmitter systems in the brain to create its alluring effects. Besides altering the release of neurotransmitters like dopamine, ethanol alters the function of a number of neurotransmitter receptors as well as transporters. When ethanol is used for longer period of time, changes in these specific neurotransmitter functions occur possibly underlying the development of alcohol dependence. Therefore, modulators of these targets of ethanol can be useful pharmacotherapeutic agents in the treatment for alcohol dependence. The aim of this review is to summarize the patent background of these potential candidates clustering them according to their mechanism of effects.

Synaptic transmission and, consequently, neurological processes are regulated by neurotransmitters and other neuro-modulators that recognize specific receptors. There are two main families of receptors that are targets for most of the compounds which act in the central nervous system (CNS); ion channel coupled receptors and G-protein coupled receptors (GPCR). The drugs that act through these receptors and are used for the treatment of different diseases related with the CNS, have traditionally been classified as agonists or antagonists. However, since the discovery of the constitutive activity of some neurotransmitter receptors during the eighties, the inverse agonist drugs have emerged as a new group of bioactive compounds with the ability to decrease receptor basal activity. New experimental evidence indicates that pathologies associated with different diseases that affect the CNS physiology could involve constitutively active receptors. Therefore, different methods and systems have been patented to explore the receptors that show high basal activity and to test the decrease of the receptor activity produced by inverse agonist compounds. In recent years some inverse agonist drugs and their targets have been patented which are capable of treating CNS related disorders. These include inverse agonists that are selective for serotonin or histamine receptors aimed at treating neuropsychiatric disorders, cannabinoids with an anorexigenic effect and inverse agonists selective for gabaergic receptors for the treatment of neurodegenerative or cognitive disorders.

Neurons are highly asymmetric cells, specialized to transmit and receive information through axons and dendrites. Neuronal morphology is determined by a particular cytoskeletal organization that provides the framework for distinct axonal and dendritic structures. Dynamic cytoskeletal rearrangements occur during neurite outgrowth, neuronal plasticity and synaptic connectivity. In this work, we summarize the evidences that support that these dynamic changes are mainly governed by phosphorylation-dephosphorylation equilibrium of cytoskeleton and cytoskeletal-associated proteins. In addition, we describe evidence supporting that in neurodegeneration an imbalance of this equilibrium occurs, followed by disarray of the cytoskeleton in axons and dendrites with the consequent disruption of synaptic connectivity. Finally we discuss current strategies and patents that could contribute to re-establish a balance in the brain of patients with dementia.