Current Pharmaceutical Design - Volume 8, Issue 10, 2002

Because of its widespread involvement in the physiology and pathology of the CNS, the glutamatergic system has gained considerable attention as a potential target for development of new agents for a number of therapeutic indications. In this respect, the glutamate receptor subtype of the NMDA type has been most intensively studied. The present review describes the rational for developing amino-alkyl-cyclohexanes, as new uncompetitive NMDA receptor antagonists based on our positive experience with memantine which has been used clinically for many years for the treatment of neurodegenerative dementia. Many amino-alkyl-cyclohexane derivatives have been evaluated in vitro and in animal models, and in turn, one structure, namely neramexane HCl (MRZ 2 / 579) was selected for further development. This agent shows some similarity to memantine e.g. channel blocking kinetics, voltage dependency, and affinity. Preclinical tests indicated particularly good activity in animal models of alcoholism (self-administration, withdrawal-induced audiogenic seizures etc.) and pain (chronic pain, inhibition of tolerance to the analgesic effects of morphine). It turn, this agent has recently entered phase II of clinical trials in alcoholism after a favourable profile seen in phase I studies.

NR2B antagonists have received considerable attention in recent years. In this class of excitatory amino acid receptor antagonists NR2B antagonists have shown efficacy in neuroprotection, anti-hyperalgesic and anti-Parkinson animal models. Several groups are involved in developing these compounds as therapeutic agents and evaluating newer therapeutic targets for these agents. Until recently benzylpiperidine and phenylpiperidine templates, which were based on the structures of Ifenprodil and Eliprodil, formed the basis of most SAR in this area. A few chemical leads in this class such as CP-101,606, Ro25,6981 and PD0196860 have been identified as possible development leads which have generated significant interest in this area. In addition to the efforts of Pfizer (Parke-Davis), Roche and E.Merck, several other industrial and academic research groups have continued to work in the NR2B area and recently Merck and Roche have reported new chemical leads as NR2B antagonists with significantly different biaryl templates. These new advances have raised hope, for potential success of the NR2B antagonists as new therapeutic agents, for the treatment of several pathophysiological indications.

It is generally agreed that (S)-glutamic acid (Glu) receptors are involved in the development of a number of diseases in the central nervous system (CNS), and ligands that interact with these receptors are of significant interest. Selective ligands are indispensable as tools for the elucidation of the physiological role of AMPA receptors and as leads for the development of therapeutic agents. Over the last decade a wide variety of such ligands have been developed and studies on the structure-activity relationships of these compounds have contributed to our understanding of the mechanisms involved in AMPA receptor activation and blockade. Series of selective agonists using the 3-isoxazolol amino acid ibotenic acid (2) as a lead compound have been designed and developed. Other heterocycles, such as the uracil moiety of willardiine (6), have also proved to be highly effective bioisosteres for the distal carboxyl group of Glu.For a number of reasons, the development of competitive antagonists with therapeutic potential has been hampered for example due to the limited solubility of key heterocyclic compounds structurally unrelated to Glu. However, some problems have been overcome, and series of water-soluble, potent and selective quinoxalinediones, indenoimidazones and isatine oximes have now been developed.At the turn of the millennium the crystal structure of GluR2 co-crystallized with different AMPA receptor ligands became available, opening a new era in the design of AMPA receptor ligands on a rational basis.

Interest in kainate receptors has increased over the past few years. Our understanding of their physiology and pharmacology has improved markedly since their original cloning and expression in the early 1990s. For example, agonist profiles at recombinant kainate receptors have been used to identify and distinguish kainate receptors in neurons. Furthermore, the development of selective antagonists for kainate receptor subtypes has increased our understanding of the functional roles of kainate receptors in neurons and synaptic transmission.In this review we described the activity of agonists and antagonists at kainate receptors and their selectivity profiles at NMDA and non-NMDA receptors.

The recent literature on the antinociceptive action of ionotropic glutamate receptor antagonists is reviewed with special emphasis on their clinical potential. Actually the glutamatergic pathways descending from the brain stem into the spinal cord may generate analgesia. However, physiologically more important is that glutamate and aspartate are apparently the main neurotransmitters along the ascending nociceptive pathways in the spinal cord. Glutamate, aspartate and their receptors can be detected in particularly high concentrations in the dorsal root ganglia and the superficial laminae (I, II) of the spinal cord. In low doses glutamate receptor antagonists only slightly elevate the threshold of the physiological pain sensation. However, they suppress the process of pathological sensitisation i.e. lowering of the pain threshold seen upon excessive or lasting stimulation of C-fibre afferents, a process that takes place during inflammation or other kinds of tissue injury. At electrophysiological level antagonists of both the NMDA- and AMPA / kainate receptors inhibit “wind up” i.e. lasting activation of the polymodal, second-order sensory neurones in the deeper layers of the dorsal horn. During sensitisation the resting Mg++ blockade of transmembrane Ca++channels is abolished, certain second messenger pathways are activated, the transcription of many genes is enhanced leading to overproduction of glutamate and other excitatory neurotransmitters and expression of Na+ channels in the primary sensory neurones activated at lower level of depolarisation. This cascade of events leads to increased excitability of the pain pathways. NMDA antagonists are apparently more potent in experimental models of neuropathic pain, whereas AMPA antagonists are more effective in abolition of hyperalgesia seen during experimental inflammation. Clinically, of the previously known NMDA antagonists amantadine, dextromethorphan and ketamine have been tested, the latter extensively. Ketamine has been found quite active in certain cases of neuropathic pain and it reduced the opiate demand when used for postoperative analgesia. However, in other types of clinical pain their efficacy is less convincing. Not being registered there are no clinical data on the AMPA antagonists. There are, however, some investigational new drugs and some novel compounds in the stage of preclinical development which antagonise the AMPA receptors in competitive fashion or allosterically. Of the latter molecules 2,3-benzodiazepines are particularly promising.

The discovery of the selective AMPA antagonist character of 2,3-benzodiazepine derivative GYKI 52466 (5) in the late eighties and the recognition of the non-competitive nature of its mode of action some years later set off the world-wide search for novel class of drugs. Notably the quest to develop new antiepileptic and neuroprotective medicines, which allosterically inhibit the AMPA sensitive glutamate operated channels. This review summarises our present knowledge about the allosteric site, dubbed “GYKI site” where the 2,3-benzodiazepines are supposed to bind to. The structure-activity relationships among AMPA antagonist 2,3-benzodiazepines and their structural analogues with similar biological profile are reviewed in a possibly comprehensive fashion. The chemical synthesis of 2,3-benzodiazepines is shortly described. The in vitro and in vivo experimental methods used for pharmacological characterisation of the biologically active compounds are briefly explained. Finally the therapeutic potential of 2,3-benzodiazepines i.e. the main fields of their clinical utility are outlined with special regard to talampanel (20) in the light of the ongoing clinical trials with this new drug candidate.

Ischaemic stroke of the brain accounts for about one third of all deaths in industrialized countries. Many of the patients who survive are severily impaired. Thus, there is an enormous need for pharmacotherapy for the treatment of ischaemic stroke.Why is such a treatment not available yet? Are the pathophysiological sequelae of brain ischaemia not well understood? Have there been no attempts for clinical development of neuroprotective drugs? Everyone who is engaged in stroke research knows that the opposite is true: The cellular processes occuring after brain ischaemia have been studied for a long time, and we have a thorough understanding of the cellular processes which are involved. Many compounds underwent clinical trials, but most of them failed. One hypothesis to explain this disappointing fact might be that the cellular consequences of stroke are manyfold, but that the clinically tested compounds were selective for only one molecular mechanism.The aim of this review is to give a summary of the pathophysiological mechanisms which occur during and after an ischaemic stroke, and to comment on the preclinical studies where multiple disease-related mechanisms were targeted pharmacologically. Moreover, a novel class of neuroprotective compounds, the oxadiazole derivatives, will be presented. Compounds of this chemical class target two key mechanisms which are important for the pathophysiology of stroke, namely voltage-gated sodium channels, as well as glutamate receptors of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype.