Current Medicinal Chemistry - Central Nervous System Agents - Volume 1, Issue 3, 2001

Cytokines are proteins that play an important role in the control of different diseases but, produced in excess or in the wrong site, they can cause pathological changes. The existence of the basic effector subsets of proinflammatory and anti-inflammatory cytokines is now well accepted, and is being used to plan therapeutic strategies for inflammatory and autoimmune disorders. Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system (CNS). It is considered as an autoimmune disease associated with immune activity directed against CNS antigens. Immune mechanisms involving proinflammatory cytokines are believed to play an important role in the pathogenesis of MS. Thus, immunosuppression and immunomodualtion have become a focus of therapeutic strategies in MS. Recombinant interferon-beta (IFN-β) has been introduced as a drug and was considered to be the first breakthrough in the treatment of multiple sclerosis. Placebo-controlled, double-blind studies, have demonstrated the efficacy of three different forms of IFN-β administrated by either subcutaneous or intramuscular routes and at different doses in patients with active relapsing-remitting MS (RR-MS). These drugs are IFN-β-1b (Betaferon) and IFN-β-1a (Avonex and Rebif). Different clinical trials demonstrated clear benefits of IFN-β for decreasing relapses and probability of sustained clinical disability progression in patients with RR-MS as assessed by brain magnetic resonance imaging (MRI). Beneficial effects in secondary progressive MS (SP-MS) was also reported. This review addresses the introduction of cytokines as novel and effective therapeutic agents as demonstrated by IFN-β in the treatment for MS. Further evaluation for combination of therapeutic immunomodulatory agents should be considered.

Cholecystokinin (CCK) is involved in essential physiological processes, through its interaction with two receptors (CCK1, CCK2). Numerous CCK2-selective agonists and antagonists have been synthesised however, the therapeutic interest for CCK2 ligands has remained focused on antagonists, endowed with anxiolytic or antiulcer properties, and capable of potentiating the analgesic effects of morphine fewer research has been directed on CCK2 agonists, generally anxiogenic.Although CCK2 receptors have been proved to be structurally homogeneous, increasing data support their functional heterogeneity. Thus, various studies have proved the occurrence of several affinity states, and different transduction pathways, associated with CCK2 receptors. Most importantly, different pharmacological profiles have been associated with CCK2 agonists, some being anxiogenic and, thus, devoid of therapeutic interest (“CCK2A” agonists). However, some CCK2 agonists revealed non-anxiogenic and memory-reinforcing. Only one such “CCK2B” agonist, the heptapeptide BC264, had been available for ten years, but recent developments led to shorter compounds, which renew the therapeutic perspectives associated to CCK2 agonists. Such an accumulation of data sets the problem of establishing a coherence between all these results in fact, the molecular basis underlying the pharmacological profiles linked to CCK2 receptor activation is not yet fully understood we will describe and discuss in this review the hypotheses suggested in this field, at the light of the data available for CCK1 receptors, which is much less debated. Some future axes of research will also be sketched, in order to progress further towards the clinical use of the favourable CCK2B agonist pharmacological profile.

The neurotrophic factors are proteins that enhance neuronal survival, differentiation, neurotransmitter function and resistance to neurotoxins and lesion. For these reasons the neurotrophic factors are considered as a new potential therapeutic tool for the treatment of neurodegenerative disorders, a group of diseases that produce the most important cause for disability in the Western world.Neurotrophic factors are used in vitro and in vivo models of neurodegenerative disorders. In this context the results of the treatment with neurotrophic factors is very reassuring. Several neurotrophic factors reached the stage of investigation in primate models of neurological disorders and some of them have been used in humans with these diseases. The results so far obtained in humans have been disappointing for several reasons including technical problems for delivery, unbearable side effects or lack of efficacy. Future approaches for the use of neurotrophic factors in humans should include the following :1. Testing of the putative compounds in animal models more related to the pathophysiology of each disease, such as genetic models of neurodegenerative diseases.2. New methods of delivery, including genetic engineering by viral vectors and administration through implantation devices.3. Better methods of testing, including the novel neuroimaging techniques.

Since the early nineties the number of scientific papers dealing with the applications of artificial neural networks (ANNs) in medicinal chemistry and medicine fields has been dramatically increasing. In this review, the applications of artificial neural networks in QSAR, concerning the classification or prediction of a biological activity, conformation searching, receptor docking and molecular design, are reviewed over the last five years. The different models of neural network used, the selection of descriptors, the comparison of results obtained by employing ANNs and other computational methods in QSAR studies, are commented. An overview of the new computer program (CODES) to generate molecular descriptors by encoding organic molecules, which are useful inputs of neural networks, is provided.