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.
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 α4β2 (Hα4β2) and human α3β4 (Hα3β4) nicotinic receptors. In the following studies, the effects of novel sulfonylpiperazine analogs that act as negative allosteric modulators on both Hα4β2 nAChRs and Hα3β4 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 Hα4β2 nAChRs.
Aripiprazole is a recently approved drug for treating schizophrenia. It is often referred to as a 3rd generation antipsychotic with unique clinical and biological properties. Its mechanism(s) of action has been attributed to either functionally selective properties or low partial agonist activity for D2 receptor signaling. We have now evaluated the ability of aripiprazole, and 12 structurally related analogs (Vangveravong et al., 2011), to regulate D2 receptor‐β‐arrestin‐2 interactions, an important signaling arm of the D2 receptor. Two assays were employed to detect receptor‐arrestin interactions: 1) a bioluminescent resonance energy transfer (BRET) assay; and 2) a β‐galactosidsase complementation assay. In each assay, dopamine (DA) stimulates D2 receptor‐β‐arrestin interactions in a dose‐dependently. None of the aripiprazole derivatives exhibited agonist activity, although each fully antagonized the DA response. Interestingly, when the DA dose‐response curves were performed with increasing concentrations of test ligand (Schild experiments), aripiprazole and four derivatives were found to decrease the ECMAX without affecting the EC50 of DA (non‐competitive inhibition). In contrast, eight derivatives of aripiprazole decreased the EC50 of DA without affecting the ECMAX (competitive inhibition). The structure‐activity relationships for these effects are currently under investigation.
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