Kappa opioid receptor (KOR) modulation is a promising target for drug discovery efforts due to KOR involvement in pain, depression, and addiction behaviors. We recently reported a new class of triazole KOR agonists that displays significant bias toward G protein signaling over βarrestin2 recruitment; interestingly, these compounds also induce less activation of ERK1/2 map kinases than the balanced agonist, U69,593. We have identified structure–activity relationships around the triazole scaffold that allows for decreasing the bias for G protein signaling over ERK1/2 activation while maintaining the bias for G protein signaling over βarrestin2 recruitment. The development of novel compounds, with different downstream signaling outcomes, independent of G protein/βarrestin2 bias, provides a more diverse pharmacological toolset for use in defining complex KOR signaling and elucidating the significance of KOR-mediated signaling.
Optimization of the sulfonamide-based kappa opioid receptor (KOR) antagonist probe molecule ML140 through constraint of the sulfonamide nitrogen within a tetrahydroisoquinoline moiety afforded a marked increase in potency. This strategy, when combined with additional structure-activity relationship exploration, has led to a compound only six-fold less potent than norBNI, a widely utilized KOR antagonist tool compound, but significantly more synthetically accessible. The new optimized probe is suitably potent for use as an in vivo tool to investigate the therapeutic potential of KOR antagonists.
The chick anxiety-depression model is a hybrid simulation, which may prove useful as an early preclinical dual pharmacological screen for novel therapeutics. Separate dose-response studies were conducted with seven test compounds that have screened positive for antidepressant effects in rodent depression models and included prasterone (5.0-40.0 mg/kg), memantine (2.5-20.0 mg/kg), ketamine (1.0-10.0 mg/kg), mifepristone (50.0-400.0 mg/kg), DOV216,303 (5.0-20.0 mg/kg), CGP36742 (2.5-15.0 mg/kg), and antalarmin (1.0-30.0 mg/kg). Chicks aged 4-6 days posthatch received test compounds intramuscularly 15 min before social separation, in which distress vocalization rates were recorded. High rates of vocalization in the first phase (0-5 min) of social separation seem to model an anxiety-like state and lower rates of vocalization in the second phase (30-60 min) seem to model a depression-like state. Prasterone, memantine, ketamine, and DOV216,303 attenuated and CPG36742 enhanced the pattern of vocalizations in the first phase. Prasterone, ketamine, mifepristone, DOV216,303, and CPG36742 attenuated and memantine and antalarmin enhanced the pattern of vocalizations in the second phase. This pattern of drug effects parallels what clinical data exist, and highlights two important characteristics of this dual-screening assay. For the compounds tested, this chick model identified phase II and III clinical failures (e.g. memantine and antalarmin) and has the potential to reveal possible contraindications of compounds (i.e. CPG36742) in cases where anxiety symptoms are concomitant with a depressive episode.
Despite the popularity of active learning applications over the past few decades, few activities have been reported for the field of medicinal chemistry. The purpose of this study is to report a new active learning activity, describe participant contributions, and examine participant performance on the assessment questions mapped to the objective covered by the activity. In this particular activity, students are asked to design two novel corticosteroids as a group (6–8 students per group) based on the design characteristics of marketed corticosteroids covered in lecture coupled with their pharmaceutics knowledge from the previous semester and then defend their design to the class through an interactive presentation model. Although class performance on the objective mapped to this material on the assessment did not reach statistical significance, use of this activity has allowed fruitful discussion of misunderstood concepts and facilitated multiple changes to the lecture presentation. As pharmacy schools continue to emphasize alternative learning pedagogies, publication of previously implemented activities demonstrating their use will help others apply similar methodologies.
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