Current drug targets. CNS and neurological disorders最新文献

The blood-brain barrier (BBB) used to be considered impermeable to polypeptides. However, this view has evolved rapidly over the past two decades. Not only do polypeptides have the potential to serve as carriers for selective therapeutic agents, but they themselves may directly cross the BBB after delivery into the bloodstream to become potential treatments for a variety of CNS disorders, including neurodegeneration, autoimmune diseases, stroke, depression, and obesity. The interactions of polypeptides with the BBB can take many forms, such as simple diffusion, saturable transport, or facilitation of entry of another peptide or protein. In some instances, interactions in the blood compartment (outside the BBB) or within the endothelial cells (at the BBB level) can significantly impede the passage of polypeptides across the BBB. We shall review the different aspects of interactions between peptides/proteins and the BBB that affect their delivery as potential drugs in their natural form, and discuss recent advances in the cell biology of polypeptide transport across the BBB. Better understanding of the BBB will provide insight and direction for future research in the treatment of CNS disorders.

Among the neuropathological features of Alzheimer's disease (AD), are senile plaques and dysfunction of cholinergic neurotransmission are the major hallmarks. Senile plaques are formed by amyloid beta-peptides (Abeta), derived from amyloidogenic processing of a larger protein named amyloid precursor protein (APP). It has been suggested and also proved that cholinergic system plays an important role in the cognitive function of the brain and its deficit correlates well with the cognitive impairment of AD. Aging is the most important risk factor for AD. In normal aging, cholinergic system undergoes degeneration. APP processing changes with aging, probably resulting in higher amyloidogenic products. The current clinical treatments for Alzheimer's disease solely rely on cholinomimetic drugs i.e., acetylcholinesterase inhibitors. Recently, a great effort has been made to seek therapies that could reduce Abeta products by influencing APP processing. Through genetic engineering in cell lines and mice, in vitro and in vivo models for AD studies have been created. Experimental evidence obtained from the studies on these model organisms suggests that activity of cholinergic neurotransmission might have an impact on APP processing. On the other hand, the proteolytic products of APP have also been found able to influence the cholinergic system in both in vitro and in vivo models. To determine whether there exists a reciprocal interaction between cholinergic neurotransmission and APP processing is important for the development of new therapeutic strategies with high efficacy and specificity for AD.

While it has long been documented that nicotine contained in tobacco leaves gives rise to major public health problems it has also been observed that this alkaloid can have beneficial effects. However, it is only with the identification of a family of genes coding for the neuronal nicotinic acetylcholine receptors and increased knowledge of their expression and function in the central nervous system that these receptors have received attention concerning their potential as drug targets. In light of the latest findings about nicotinic acetylcholine receptors and their involvement in disease states we review the possibility to design new drugs targeted to these ligand-gated channels. Beneficial and possible undesirable actions of agonists, antagonists and allosteric modulators are discussed and placed in perspective of our most recent knowledge.

Transglutaminases (TGases) belong to a family of closely related proteins that catalyze the cross linking of a glutaminyl residue of a protein/peptide substrate to a lysyl residue of a protein/peptide co-substrate with the formation of an Nepsilon-(gamma-L-glutamyl)-L-lysine [GGEL] cross link and the concomitant release of ammonia. Such cross-linked proteins are often highly insoluble. Neurodegenerative diseases, such as Alzheimer disease (AD), Parkinson disease (PD), supranuclear palsy and Huntington disease (HD), are characterized in part by aberrant cerebral TGase activity and by increased cross-linked proteins in affected brain. In support of the hypothesis that TGases contribute to neurodegenerative disease, a recent study shows that knocking out TGase 2 in HD-transgenic mice results in increased lifespan. Moreover, recent studies show that cystamine, an in vitro TGase inhibitor, prolongs the lives of HD-transgenic mice. However, these findings are not definitive proof of TGase involvement in HD neuropathology. In neurodegenerative diseases, the brain is under oxidative stress and cystamine can theoretically be converted to the potent antioxidant cysteamine in vivo. Cystamine is also a caspase 3 inhibitor. In addition to neurodegenerative diseases, aberrant TGase activity is associated with celiac disease. Interestingly, a subset of celiac patients develops neurological disorders. This review focuses on the strategies that have been recently employed in the design of TGase inhibitors, and on the possible therapeutic benefits of selective TGase inhibitors to patients with neurodegenerative disorders or to patients with celiac disease.

Substance P (SP) is a neuropeptide with a known involvement in anxiety and nociception processes, which acts through the activation of neurokinin-1 (NK(1)) receptors. Recently, a NK(1) receptor antagonist has been shown to display antidepressant activity comparable to that of the selective serotonin reuptake inhibitor paroxetine, but with a better side effect profile. Given their lack of affinity for monoamine transmitters, the antidepressant role of NK(1) receptor antagonists has been attributed to a unique mechanism. However, monoaminergic neurons receive an important SP innervation and also posses NK(1) receptors (noradrenergic neurons of the locus coeruleus) or are in close apposition to NK(1)-containing cells (serotonergic neurons of the dorsal raphe nucleus). In addition, NK(1) receptors are expressed in brain regions involved in the regulation of affective behaviours and the neurochemical response to stress. For these reasons, it has also been postulated that the purported antidepressant action of NK(1) receptor antagonists may result from the modulation of such brain monoaminergic systems. Indeed, systemic administration of NK(1) receptor antagonists enhances the firing rate of dopaminergic, noradrenergic and serotonergic neurons. This effect on serotonergic cells is seen consistently only after long-term treatment and has been associated with a functional desensitisation of somatodendritic 5-HT(1A) autoreceptors. Mice lacking NK(1) receptors also show an increased basal firing rate of 5-HT cells in vivo. These observations are suggestive of a predominating inhibitory role of SP upon monoaminergic neurons under physiological conditions and would provide support for the antidepressant activity of NK(1) receptor antagonists, although this may be achieved through an indirect action on other transmitter systems. The possibility that this class of drugs can modulate the function of only certain serotonergic pathways could be the basis of their better side effect profile. However, although preliminary studies showed some therapeutic efficacy for NK(1) receptor antagonists, the first compound developed (MK-869) has been discontinued from Phase III trials because it was not more effective than placebo in the treatment of depression. Further research is needed to ascertain whether the mechanism of action of NK(1) receptor antagonists may be relevant to the antidepressant treatment.

Somatostatin (somatotropin release inhibitory factor; SRIF) initiates its biological activity by interacting with a family of highly homologous integral membrane receptors (sst(1) -sst(5)). SRIF neuronal actions regulate protein phosphorylation levels, control second messenger production and modulate neuronal membrane potential. Recently, our understanding of SRIF neurobiology has been driven by new pharmacological and molecular biological tools. SRIF receptor subtype specific antibodies have identified a distinctive, yet overlapping, expression pattern for this receptor family, with multiple subtypes co-localizing in the central and peripheral nervous system. This complex expression profile has confounded efforts to establish each receptor's role in the nervous system in part by the possible homo- and heteroligomerization of the receptor proteins. However, the recent discovery of SRIF receptor subtype selective ligands, supplemented by in vitro and in vivo models with inactivated SRIF receptor genes, now provides opportunities to clearly delineate each receptor's neuronal role. The convergence of these pharmacologic, immunologic and molecular biologic approaches extend our understanding of SRIF neurobiology while promising new therapeutic avenues for SRIF research.

Several types of voltage- or ligand-activated calcium channels contribute to the excitability of neuronal cells. Low-voltage-activated (LVA), T-type calcium channels are characterised by relatively negative threshold of activation and therefore they can generate low-threshold spikes, which are essential for burst firing. At least three different proteins form T-type calcium current in neurons: Ca(v)3.1, Ca(v)3.2 and Ca(v)3.3. Expression of these proteins in various brain regions is complementary. Individual channel types could be distinguished by different sensitivity towards inorganic cations. This inhibition can contribute to the toxicity of some heavy metals. Selective inhibition of T-type calcium channels by organic blockers may have clinical importance in some forms of epilepsy. Mibefradil inhibits the expressed Ca(v2)3.1, Ca(v)3.2 and Ca(v)3.3 channels in nanomolar concentrations with Ca(v)3.3 channel having lowest affinity. The sensitivity of the expressed Ca(v)3.1 channel to the antiepileptic drugs, valproate and ethosuximide, is low. Ca(v)3.1 channel is moderately sensitive to phenytoin. The Ca(v)3.2 channel is sensitive to ethosuximide, amlodipine and amiloride. All three LVA calcium channels are moderately sensitive to active metabolites of methosuximide, i.e. alpha-methyl-alpha-phenylsuccinimide. Several neuroleptics inhibit all three LVA channels in clinically relevant concentrations. All three channels are also inhibited by the endogenous cannabinoid anandamide. A high affinity peptide blocker for these Ca channels is the scorpion toxin kurtoxin which inhibits the Ca(v)3.1 and Ca(v)3.2, but not the Ca(v)3.3 channel in nanomolar concentrations. Nitrous oxide selectively inhibits the Ca(v)3.2, but not the Ca(v)3.1 channel. The Ca(v)3.2, but not the Ca(v)3.1 channel is potentiated by stimulation of Ca(2+)/CaM-dependent protein kinase.

The 5-hydroxytryptamine(6) (5-ht(6)) was one of the most recent additions to the 5-HT receptor family, selective antagonists have recently been developed and potential functional roles are now becoming apparent. The high affinity of a wide range of psychiatric drugs for the 5-ht(6)receptor, together with its almost exclusive expression in the CNS, being abundant in limbic and cortical regions, has stimulated significant research interest. The 5-ht(6)receptor appears to regulate glutamatergic and cholinergic neuronal activity, and increasing evidence suggests that it may be involved in the regulation of cognition, feeding and, possibly, affective state and seizures. The current article will review all aspects of the discovery, genetics, distribution, pharmacology and function of the 5-ht(6)receptor. Taken together, this wealth of information warrants the use of the upper case nomenclature for the 5-ht(6) receptor to be approved and its true status recognised.

Among the seven classes of serotonin (5-hydroxytryptamine, 5-HT) receptors which have been identified to date, the 5-HT(1) class is comprised of five receptor types, with the 5-HT(1A), 5-HT(1B) and 5-HT(1D) characterized by a high affinity for 5-carboxamido-tryptamine, the 5-HT(1E) and 5-HT(1F) characterized by a low affinity for this synthetic agonist, and all five having a nanomolar affinity for the endogenous indolamine ligand. The genes encoding 5-HT(1) receptors have been cloned in both human and rodents, allowing the demonstration that they all belong to the G-protein-coupled receptor super-family with the characteristic 7 hydrophobic (transmembrane) domain-containing amino acid sequence. All the 5-HT(1) receptor types actually interact with G alpha i/G alpha o proteins to inhibit adenylyl cyclase and modulate ionic effectors, i.e. potassium and/or calcium channels. Probes derived from the knowledge of amino acid sequence of the receptor proteins and of nucleotide sequence of their encoding mRNAs allowed the mapping of all the 5-HT(1) receptor types in the central nervous system and other tissues. For the last twenty years, both pharmacological investigations with selective agonists and antagonists and phenotypical characterization of knock-out mice have been especially informative regarding the physiological implications of 5-HT(1) receptor types. This research ends notably with the development of triptans, whose agonist activity at 5-HT(1B), 5-HT(1D) and 5-HT(1F) receptors underlies their remarkable efficacy as antimigraine drugs. Clear-cut evidence of the implication of 5-HT(1) receptors in anxiety- and depression-like behaviours and cognitive performances in rodents should hopefully promote research toward development of novel drugs with therapeutic potential in psychopathological and dementia-related diseases.

5-HT(3)-receptor antagonists are highly selective competitive inhibitors of the 5-HT(3)-receptor with negligible affinity for other receptors. They are potent, rapidly absorbed and easily penetrate the blood-brain barrier; metabolized by the cytochrome P450-system with half-life varying from 3-10 hours. The compounds investigated so far do not modify normal behaviour in animals or man and are well tolerated over wide dose ranges, the most common side effects being headache or constipation. Clinical efficacy was first established in chemotherapy-induced emesis (and then in radiotherapy-induced and post-operative emesis), where 5-HT(3)-receptor antagonists set a new standard of antiemetic efficacy and tolerability. The 5-HT(3) receptor antagonists, via a central and / or peripheral action, have been shown to reduce secretion and motility in the gut and possess clinical utility in irritable bowel syndrome, and possibly other visceral pain disorders. Their value in fibromyalgia is being evaluated. In preclinical behavioural assays they induce effects consistent with anxiolysis, improved cognition, anti-dopaminergic activity and use in drug abuse and withdrawal. There is some evidence that ondansetron may reduce alcohol consumption in moderate alcohol abusers but overall, 5-HT(3) receptor antagonists seem to be of limited use in psychiatric disorders: where effects have been seen, they seem to be unusually sensitive to dose and stage of disease. Nevertheless, their antiemetic potential has been of great benefit to cancer patients and the possible extension of their use to bowel disorders may yet fulfil their initial exciting promise.