Current Medicinal Chemistry - Central Nervous System Agents - Volume 5, Issue 3, 2005

The main component of the amyloid plaque is insoluble Aβ1-42 (Aβ42), which adopts a structure rich in antiparallel β-pleated sheets. Recently, increasing awareness of Aβ intermediates as molten-globule states has paralleled insight into the biological activities of the Aβ conformer. The molten-globule state of Aβ42 displays a less ordered, metastable conformation that is stabilized by the formation of fibrils. The molten-globule state of the protein has many biological properties and understanding the mechanisms of its formation is an important step in devising a therapeutic strategy for Alzheimer's disease. There have been many studies of the biological properties of Aβ42 such as self-aggregation, binding to other proteins such as apolipoprotein E, cytotoxicity for neuronal cells, vasoconstriction, oxidative activity with superoxide-mediated singlet-oxygen intermediate and proteolytic activity against casein. Recent studies demonstrated that α-1 anti-chymotrypsin, a member of the serine protease inhibitor (serpin) family is also involved in the amyloid plaque. In this review, we focused on the serine protease-like activity of Aβ42 for casein substrate and the effect of bio-essential metal ions for the activity and also suggest its inhibition with Aβ42 derivatives; Aβ15-22 (QKLVFFAE) which is a potential fragment to prevent Aβ self-aggregation. Consequently, we suggest that the short peptides of this kind may be of use in the therapy of Alzheimer's disease.

Deficient inhibitory processing of the P50 auditory evoked potential is a measurable marker observed in schizophrenia. Several lines of evidence suggest that α7 nicotinic receptors (α7 nAChRs) play a critical role in P50 auditory sensory gating in the human brain. Similar to schizophrenic patients, DBA/2 mice spontaneously exhibit a deficit in inhibitory processing of the P20-N40 auditory evoked potential, which is a rodent analogue of the human P50 auditory evoked potential. Agonists at α7 nAChRs improve deficient inhibitory processing of the P20-N40 auditory gating potential in DBA/2 mice. In this article, we review the role of α7 nAChRs in the pathophysiology of schizophrenia, and α7 nAChR agonists and indirect agonists (5-hydroxytryptamine-3 (5-HT3) receptor antagonists, positive allosteric modulators (galantamine, 5-hydroxyindole, PNU-120596), FK960, FR236924) at α7 nAChRs as potential therapeutic drugs for the treatment of schizophrenia. In addition, we also discuss the role of kynurenic acid as an endogenous antagonist of α7 nAChRs in brain.

Advances in combinatorial synthesis and high throughput screening have resulted in libraries containing hundreds of thousands of drug candidate compounds. Computational prediction of properties that will determine the utility of a drug molecule has become a sine qua non in the pharmaceutical industry, because of the appreciation that ADMET properties must be considered early in the discovery process and the higher cost of experimental alternatives. In this paper we are reviewing the models developed recently to predict the permeation of organic molecules through the blood-brain barrier.

There is evidence suggesting that nitric oxide (NO) may play an important role in dopamine (DA) cell death. NO may act as a neuroprotector or neurotoxic agent in dopamine neurons, depending on cell redox status. Glutathione (GSH) depletion is the earliest biochemical alteration shown to date in brains of Parkinson's disease (PD) patients. However, data from animal models show that GSH depletion by itself is not sufficient to induce nigral degeneration. Low NO concentrations have neurotrophic effects on DA cells via a cGMP-independent mechanism that may implicate up-regulation of GSH. On the other hand, higher levels of NO induce cell death in both DA neurons and mature oligodendrocytes that is totally reverted by soluble factors released from glia. Alterations in GSH levels change the neurotrophic effects of NO in dopamine function into neurotoxic, under these conditions, NO triggers a programmed cell death with markers of both apoptosis and necrosis characterised by an early production of free radicals followed by late activation of the sGC/cGMP/PKG pathway. Arachidonic acid metabolism through the 12-lipoxygenase (12-LOX) pathway is also central for this GSH-NO interaction. Neurotrophism of NO switches into neurotoxicity after GSH depletion, due to persistent activation of the ERK-1/2 signaling pathway in glial cells. The implication of these cell death signaling pathways in pathological conditions like Parkinson's disease, where GSH depletion, glial dysfunction and NO overproduction have been documented, are discussed.

The accumulation of high local concentrations of excitatory amino acids, particularly glutamate, is involved in neuronal cell death in neurodegenerative diseases such as stroke, trauma, Huntington's disease, and amyotrophic lateral sclerosis. Accumulation of glutamate leads to excessive Ca2+ influx into the neuron. The molecules involved in neuronal degeneration following intracellular Ca2+ overload have been identified. Calcineurin and calpain, a Ca2+/calmodulindependent protein phosphatase and Ca2+-dependent cysteine protease, respectively, are two of the most important Ca2+- dependent effectors during neuronal degeneration. These two molecules have been thought to mediate neuronal degeneration through independent cascades. However, recent studies have shown that a cross-talk pathway exists between calcineurin and calpain in neurons and the pathway plays a critical role in excitotoxic neuronal degeneration. This review covers recent findings regarding the cross-talk pathway involved in neuronal degeneration and novel neuroprotective reagents that block the signal pathway.

Gamma-aminobutyric acid (GABA) is the most important inhibitory transmitter in the central nervous system. Most of the actions of GABA are mediated by GABAA receptors. These are choride ion channels that can be opened by GABA and can be modulated by a variety of pharmacologically and clinically important drugs. GABAA receptors are composed of five subunits that can belong to different subunit classes. So far, 19 different subunits have been identified in mammalian brain, exhibiting a distinct but overlapping regional and cellular distribution and giving rise to an enormous heterogeneity of GABAA receptors. Depending on the subunit composition these receptors exhibit distinct electrophysiological and pharmacological properties. Drugs in clinical use are only weakly receptor subtype selective, explaining their similar and broad pharmacological effects. Investigations of mice with a point mutation in a GABAA receptor subunit that eliminates the actions of drugs on certain receptors, only, have indicated that different receptor subtypes mediate distinct actions of GABAergic drugs. This conclusion was supported by experiments with newly developed compounds exhibiting a significantly increased receptor subtype selectivity, suggesting a tremendous clinical potential of drugs with high selectivity for certain receptor subtypes. In addition, the recent availability of structural information on GABAA receptors from homology modeling studies will stimulate experiments leading to the identification of the binding sites of the various GABAA receptor ligands. Accumulating structural information on receptor subtypes will finally lead to more precise pharmacophore models that will provide the basis for a more rational drug design.