Current topics in medicinal chemistry
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Voltage-gated sodium channels are encoded by a family of ten structurally-related genes that are expressed in spatially and temporally distinct patterns, mainly in excitable tissues. They underlie electrical signalling in nerve and muscle. It has long been known that sodium channel blockers are anaesthetics as well as powerful analgesics when delivered at low concentrations. ⋯ There are indications that sodium channel blockers may also be useful in affective disorders and schizophrenia. The production of tissue-specific and eventually inducible knock out mice as well as genetic studies has proved useful in understanding the specialised role of individual types of sodium channels. The development of sub-type specific blockers has proved slower than anticipated, although the properties of naturally occurring toxin blockers suggest that subtype-specific blockers of sodium channels could be very useful clinically in the treatment of pain.
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Management of pain is an essential aspect of medicine; however, current therapies are frequently insufficient owing to severe side effects or limited effectiveness. Therefore, the discovery of new analgesics is needed, especially to treat the proportion of painful patients poorly improved by available analgesics. The transmission of nociceptive stimuli in primary afferent neurons critically depends on a peculiar repertoire of various types of ion channels such as a number of TRP channels, persistent sodium channels, inwardly rectifying potassium channels and voltage-gated calcium channels that either detect noxious stimuli, or regulate cellular excitability and synaptic transmission. ⋯ Hence, these channels are considered key targets for the development of analgesics. The nervous system expresses multiple types of calcium channels with specialized roles in neurophysiology. Here, we review the role of these channels and their accessory subunits in nociceptive signaling, and their potential as targets for development of innovative analgesics.
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The importance of the GABAergic system in spinal nociceptive processing has long been appreciated but we have only recently begun to understand how this system is modulated by the regulation of anion gradients. In neuronal tissues, cation-chloride cotransporters regulate Cl- homeostasis and the activity and/or expression of these transporters has important implications for the direction and magnitude of anion flow through GABA-A channels. ⋯ On the other hand, KCC2 expression is reduced in dorsal horn neurons following peripheral nerve injury resulting in a loss of GABA-/glycinergic inhibitory tone and, in some cases, inverting its action into net excitation. Pharmacological targeting of these cation chloride cotransporters to restore normal GABA-/glycinergic transmission in the spinal cord represents an entirely novel approach to the development of analgesics.
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Non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 inhibitors (Coxibs) are commonly used for minor pain treatment and chronically in the management of rheumatoid arthritis and osteoarthritis. Three areas of safety concerns are shared by both groups of drugs: Gastrointestinal complications (upper gastrointestinal bleeding, perforations or obstruction), cardiovascular safety (mainly myocardial infarction) and renal safety (acute renal failure, hypertension and electrolyte abnormalities). The incidence of renal complications may be increased two-fold with NSAIDs or coxibs, and there is no evidence for a major difference between the two groups of drugs. ⋯ In contrast, coxibs may be associated with a greater incidence of cardiovascular complications, mainly myocardial infarction, especially in comparison to certain NSAIDs such as naproxen. Thus, coxibs are not generally safer than NSAIDs. Rather, their long-term use should be customized to individual patients and their intrinsic baseline risks and other medications required in their management.
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Gamma-aminobutyric acid (GABA), one of the main inhibitory neurotransmitters in the brain, interacts with three types of receptors for GABA--GABA(A), GABA(B) and GABA(C). GABA(A) receptors, associated with binding sites for benzodiazepines and barbiturates in the form of a receptor complex, control opening of the chloride channel. When GABA binds to the receptor complex, the channel is opened and chloride anions enter the neuron, which is finally hyperpolarized. ⋯ Besides, they also inhibit sodium currents. Zonisamide, apparently sharing this common mechanism, also reduces the concentration of free radicals. Novel antiepileptic drugs are better tolerated by epileptic patients and practically are devoid of important pharmacokinetic drug interactions.