Current topics in medicinal chemistry
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The idea of selectively targeting nociceptive transmission at the level of the peripheral nervous system is attractive from multiple perspectives, particularly the potential lack of non-specific (non-targeted) CNS side effects. Out of the multiple TRP channels involved in nociception, TRPV1 is a strong candidate based on its biophysical conductance properties and its expression in inflammation-sensitive dorsal root ganglion neurons and their axons and central and peripheral nerve terminals. While TRPV1 antagonists have undergone extensive medicinal chemical and pharmacological investigation, for TRPV1 agonists nature has provided an optimized compound in RTX. ⋯ This can include routes as diverse as subcutaneous, intraganglionic or intrathecal (CSF space around the spinal cord). The present review focuses on the molecular and preclinical animal experiments that form the underpinnings of our clinical trial of intrathecal RTX for pain in advanced cancer. As such this represents a new approach to pain control that emerges from a long line of research on capsaicin and other vanilloids, their physiological actions, and the molecular biology of the capsaicin receptor TRPV1.
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Benzodiazepine site agonists (such as diazepam) are well-known to impair cognition. Since benzodiazepines exert their effects via modulation of α1-, α2-, α3- and α5-containing GABA(A) receptors, the cognition-impairing effects of diazepam must be associated with one or several of these subtypes. Of these different subtypes, α5-containing GABA(A) receptors represent an attractive option as the "cognition" subtype based upon the preferential localization of these receptors within the hippocampus and the well-established role of the hippocampus in learning and memory. ⋯ By appending features of the prototypic α2/α3-selective triazolopyridazine L-838417 (t-butyl and 1,2,4 triazole) along with the isoxazole of α5IA to a pyrazolotriazine core, an additional clinical candidate, MRK-016, was identified. Finally, a degree of α5 efficacy selectivity was achieved the pyridazine series but metabolic instability within this chemotype limited its further optimization. Overall, these studies demonstrate the feasibility of adopting a selective efficacy approach in the identification of α5 selective GABA(A) receptor inverse agonists.
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The prototypic benzodiazepines, such as diazepam, are not only anxiolytic but also produce sedation. These effects are mediated by GABA(A) receptors containing either an α1, α2, α3 or α5 subunit at which the positive modulatory effects (i.e., agonist efficacy) of benzodiazepines are mediated via a specific benzodiazepine recognition site. Recent molecular genetic and pharmacological data point to α1-containing GABA(A) receptors as the "sedative" and α2- and/or α3-containing receptors as the "anxiolytic" subtype(s). ⋯ The addition of a further nitrogen into the imidazopyrimidine core produced the imidazotriazine series, which yielded the clinical candidate TPA023B. Imidazopyrazinone and imidazotriazinone compounds offered no advantages over their respective imidazopyrimidine and imidazotriazine analogues. Additional pharmacological tool compounds were identified within the pyridine, pyrazolotriazine, pyridazine and pyrazolopyridone series highlighting the general feasibility of GABA(A) receptor subtype selective efficacy as a strategy for developing compounds with novel in vitro and in vivo profiles.
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Snakebite is a medical emergency in many parts of the world, particularly in the temperate regions. According to 2007 World Health Organization (WHO) report, there are about 5 million snakebite incidences resulting in 2.5 million envenoming, and 125,000 deaths occur annually. Most affected are the healthy individuals like children and farming populations with resource poor settings and away from health care centers in low-income countries of Africa, Asia and Latin America. ⋯ Because of dearth of knowledge, venom researchers and medical practitioners from affected countries worldwide should join together to accomplish this scenario. In view of this, the present review provides a broader perspective on the possible production and application of highly effective therapeutic master anti-venom, designing master diagnostic kit and also to deal with the inefficacy of anti-venom therapy against local manifestations and secondary complications of snakebite. The review demands thorough understanding of venom pharmacology, inculcating new strategies to handle and to enhance the efficacy of snakebite management and urge the governing systems of affected countries to take steps to curtail accidental debilitation and death rate of healthy individuals due to snakebite.