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Preface [Hot Topic: Rational Drug Design and The Discovery of the 1,2,3-Triazolines as a Unique Class of Anticonvulsants and Antiischemic Agents (Guest Editor: Pankaja K. Kadaba)]

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Abstract:

The excitatory neurotransmitter glutamate plays a central role in the development, plasticity, and repair of the CNS. The last decade known as the 'Decade of the Brain' has been a fruitful epoch in the field of glutamate receptor biology. However, many questions still remain about the true in vivo function of glutamate receptor subtype mediated signaling.

The first review by G.N. Barnes, M.D. / PhD. and J.T. Slevin, M.D. is designed to familiarize the reader with recent developments, especially those involved in neurological disease. First, the history and development of glutamate receptor biology up to the beginning of the 1990's is reviewed. Ionotropic and metabotropic glutamate receptors are discussed with particular emphasis on the NMDA, AMPA, and kainic acid ionotropic receptors. The cellular and subcellular localization, signaling cascades linked to each receptor subtype, and role in normal synaptic physiology are reviewed. The last segment of the article covers recent advances in our understanding of glutamate receptor signaling that induces changes in synaptic connectivity and function in animal models of epilepsy and stroke.

The second review by Tsung-Ping Su, Ph.D., an eminent authority on sigma receptors, along with Teruo Hayashi, Ph. D., brings attention to the biochemical and physiological roles of sigma receptors particularly sigma-1 receptors that have just begun to unveil. Sigma-1 receptors exist mainly in the central nervous system. Sigma-1 receptor ligands include cocaine, (+) benzomorphans like (+) pentazocine and (+) N-allyl-normetazocine [or (+) - (SKF-10047] and endogenous neurosteroids like progesterone and pregnenolone sulfate. Many pharmacological and physiological actions have been attributed to sigma-1 receptors. These include the regulation of IP3 receptors and calcium signaling at the endoplasmic reticulum, mobilization of cytoskeletal adaptor proteins, modulation of nerve growth factor-induced neurite sprouting, modulation of neurotransmitter release and neuronal firing, modulation of potassium channels as a regulatory subunit, alteration of psychostimulant-induced gene expression, and blockade of spreading depression. Behaviorally, sigma-1 receptors are involved in learning and memory, psychostimulant-induced sensitization, cocaine-induced conditioned place preference, and pain perception. Notably, in almost all the aforementioned biochemical and behavioral tests, sigma-1 agonists, while having no effects by themselves, caused the amplification of signal transductions incurred upon the stimulation of the glutamatergic, dopaminergic, IP3-related metabotropic, or nerve growth factor-related systems. Thus, it is hypothesized that sigma-1 receptors, at least in part, are intracellular amplifiers creating a supersensitized state for signal transduction in the biological system.

The third review by Pankaja K. Kadaba, Ph.D., the guest editor, conducts a comprehensive examination of the Δ2-1,2,3- triazoline heterocycles, a unique class of anticonvulsants and antiischemic agents. The triazolines are hypothesized to act as a group of “built in” heterocyclic prodrugs and their potential metabolites (β-amino alcohols V and VA, and α-amino acid VI) are postulated from a knowledge of their chemistry. Studies on their metabolism along with their pharmacology, have proved the prodrug hypothesis and the β-amino alcohol V has been identified as the active species; there is no proof for the formation of the α-amino acid VI. Radio-ligand binding studies indicate that the active β-amino alcohol metabolite acts as an MK- 801 / NMDA antagonist and that the triazolines act as excitatory amino acid (EAA) antagonists. The parent triazolines inhibit presynaptic glutamate release. Some triazolines show an augmentation of 50-63%, in the C1- channel activity, a useful membrane action that reduces the excessive L-Glu release that occurs during epileptic seizures. The high anticonvulsant activity of TRs in a variety of seizure models including their effectiveness in the kindling model of complex partial seizures may be due to their unique dual-action mechanism whereby the TR and V together effectively impair both pre- and postsynaptic aspects of EAA neurotransmission; thus the TRs have clinical potential in the treatment of complex partial epilepsy which is refractory to currently available drugs.

Since there is strong evidence that L-Glu plays an important role in human epilepsy as well as in brain ischemia / stroke, and since the TRs act by inhibiting EAA neurotransmission, it was logical to expect that the anticonvulsant TRs may evince beneficial therapeutic potential in cerebral ischemia resulting from stroke as well. And indeed, several TRs, when tested in the standard gerbil model of global ischemia did evince remarkable ability to prevent neuronal death.

The fourth review section, also written by Pankaja K. Kadaba, Ph.D. along with Trupti Dixit, Ph. D., elucidates the metabolism and pharmacology of the 1,2,3-triazolines (TRs) and the identification of the triazoline pharmacophore and the subsequent evolution of the aminoalkylpyridines (AAPs). The AAPs have no activity in the scMet test but are highly effective in the MES seizure test by the oral route. The AAPs bind to the σ1 receptor with low affinity, but high selectivity. They impair Glu release to the same extent as the triazolines and afforded a high degree of protection in the kindled rat. They show no affinity for the NMDA / PCP receptor sites; thus the toxic side effects of NMDA antagonists are absent in the σ selective AAPs. Variations of the heterocyclic unit, the alkyl chain and the amino group in the AAP molecules indicated that the 4- pyridyl substituent along with a methyl (alkyl) group, and a 4-C1, 3-C1 or 3,4-C12 substitution on the N-phenyl group, afforded the most active compounds.

Although the AAPs are very effective in the MES and the kindling models of epilepsy, they showed only low to moderate activity in protecting neuronal cells in stroke-induced cerebral ischemia. In the case of the TR compounds, even the least effective TR afforded 47% protection from neuronal injury. It is not known at this point, whether activity in both the MES and scMet test, which would imply a role for both Glu and GABA is a prerequisite for antiischemic activity.

Finally, I wish to take this opportunity to thank Professor Atta-ur Rahman for his gracious invitation requesting me to be guest editor for a special topics issue that will cover mostly my research efforts on central nervous system (CNS) drugs over a span of more that 35 years, particularly anticonvulsant sand antiischemic agents. I also want to thank all the authors who so kindly agreed to contribute to this special topics issue. I also thank Dr. Atif Hussain, the Manager of publications, for his continuing patience on several occasions when unexpected delays in article submission and refereeing had occurred.

Document Type: Book Review

DOI: http://dx.doi.org/10.2174/0929867033456846

Affiliations: K and K Biosciences, Inc. 2504 Century lane Chadds Ford PA 19317 USA

Publication date: October 1, 2003

More about this publication?
  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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