RESUMEN
Kappa-opioid receptors (KOR) are widely expressed throughout the central nervous system, where they modulate a range of physiological processes depending on their location, including stress, mood, reward, pain, inflammation, and remyelination. However, clinical use of KOR agonists is limited by adverse effects such as dysphoria, aversion, and sedation. Within the drug-development field KOR agonists have been extensively investigated for the treatment of many centrally mediated nociceptive disorders including pruritis and pain. KOR agonists are potential alternatives to mu-opioid receptor (MOR) agonists for the treatment of pain due to their anti-nociceptive effects, lack of abuse potential, and reduced respiratory depressive effects, however, dysphoric side-effects have limited their widespread clinical use. Other diseases for which KOR agonists hold promising therapeutic potential include pruritis, multiple sclerosis, Alzheimer's disease, inflammatory diseases, gastrointestinal diseases, cancer, and ischemia. This review highlights recent drug-development efforts targeting KOR, including the development of G-protein-biased ligands, mixed opioid agonists, and peripherally restricted ligands to reduce side-effects. We also highlight the current KOR agonists that are in preclinical development or undergoing clinical trials.
RESUMEN
Neuronal nicotinic receptors have been implicated in several diseases and disorders such as autism, Alzheimer's disease, Parkinson's disease, epilepsy, and various forms of addiction. To understand the role of nicotinic receptors in these conditions, it would be beneficial to have selective molecules that target specific nicotinic receptors in vitro and in vivo. Our laboratory has previously identified novel negative allosteric modulators of human α4ß2 (Hα4ß2) and human α3ß4 (Hα3ß4) nicotinic receptors. The effects of novel sulfonylpiperazine analogues that act as negative allosteric modulators on both Hα4ß2 nAChRs and Hα3ß4 nAChRs were investigated. This work, through structure-activity relationship (SAR) studies, describes the chemical features of these molecules that are important for both potency and selectivity on Hα4ß2 nAChRs.
