A Series of 2-((1-Phenyl-1H-imidazol-5-yl)methyl)-1H-indoles as Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising therapeutic target in cancer immunotherapy and neurological disease. Thus, searching for highly active inhibitors for use in human cancers is now a focus of widespread research and development efforts. In this study, we report the structure-based design of 2-(5-imidazolyl)indole derivatives, a series of novel IDO1 inhibitors which have been designed and synthesized based on our previous study using N1-substituted 5-indoleimidazoles. Among these, we have identified one with a strong IDO1 inhibitory activity (IC50 =0.16 µM, EC50 =0.3 µM). Structural-activity relationship (SAR) and computational docking simulations suggest that a hydroxyl group favorably interacts with a proximal Ser167 residue in Pocket A, improving IDO1 inhibitory potency. The brain penetrance of potent compounds was estimated by calculation of the Blood Brain Barrier (BBB) Score and Brain Exposure Efficiency (BEE) Score. Many compounds had favorable scores and the two most promising compounds were advanced to a pharmacokinetic study which demonstrated that both compounds were brain penetrant. We have thus discovered a flexible scaffold for brain penetrant IDO1 inhibitors, exemplified by several potent, brain penetrant, agents. With this promising scaffold, we provide herein a basis for further development of brain penetrant IDO1 inhibitors.

Antibody responses to porcine reproductive and respiratory syndrome virus, influenza A virus, and Mycoplasma hyopneumoniae from weaning to the end of the finisher stage in fourteen groups of pigs in Ontario, Canada.

BACKGROUND: Respiratory diseases are among the most important factors affecting swine farm productivity in Canada. The objectives of this study were to investigate antibody responses to porcine reproductive and respiratory syndrome virus (PRRSV), influenza A virus (IAV), and Mycoplasma hyopneumoniae (M. hyopneumoniae) from weaning to the end of the finisher stage on a subset of commercial swine farms in Ontario, Canada, and to examine the association between nursery diet and antibody responses. RESULTS: Overall, older pigs were more likely to test seropositive for PRRSV and less likely to test seropositive for M. hyopneumoniae (p <  0.001). Pigs were more likely to test seropositive for IAV at weaning and the end of the grower and finisher stages compared to the end of nursery (p <  0.001). Pigs that were seropositive for IAV were more likely to test seropositive for both PRRSV and M. hyopneumoniae (p <  0.001). Two, 9, and 4 groups that had more than 20% of pigs seropositive to PRRSV, IAV, and M. hyopneumoniae, respectively, from the end of nursery to the end of finisher were classified as seropositive. Pigs fed a plant-based (low complexity) diet during nursery were more likely to be seropositive for PRRSV (p <  0.001) but there were no significant differences in seropositivity to IAV or M. hyopneumoniae due to nursery diet complexity. CONCLUSIONS: This study provides information regarding changes in serum antibody in pigs across different stages of production and highlights periods of vulnerability. Additionally, these findings may encourage further research into the effects of nursery diet complexity on disease susceptibility and immune response.

Chronic nicotine exposure attenuates the effects of Δ9 -tetrahydrocannabinol on anxiety-related behavior and social interaction in adult male and female rats.

INTRODUCTION: Anxiogenic and anxiolytic effects of cannabinoids are mediated by different mechanisms, including neural signaling via cannabinoid receptors (CBRs) and nicotinic cholinergic receptors (nAChRs). This study examined the effects of prior nicotine (the psychoactive component in tobacco) exposure on behavioral sensitivity to delta-9-tetrahydrocannabinol (THC; the psychoactive component of cannabis) challenge in animals. METHODS: Male and female adult Sprague-Dawley rats (N = 96) were injected daily with nicotine (1 mg/kg, i.p.) or vehicle for 14 days, followed by a 14-day drug-free period. On test day, rats were injected with THC (0.5, 2.0, or 5.0 mg/kg, i.p.) or vehicle and anxiety-related behavior was assessed in the emergence (EM), elevated plus maze (EPM), and social interaction (SI) tests. RESULTS: Chronic nicotine pretreatment attenuated some of the anxiogenic effects induced by THC challenge which can be summarized as follows: (a) THC dose-dependently affected locomotor activity, exploratory behavior, and social interaction in the EM, EPM, and SI tests of unconditioned anxiety; (b) these effects of acute THC challenge were greater in females compared with males except for grooming a conspecific; (c) prior nicotine exposure attenuated the effects of acute THC challenge for locomotor activity in the EPM test; and (d) prior nicotine exposure attenuated the effects of THC challenge for direct but not indirect physical interaction in the SI tests. CONCLUSIONS: The ability of nicotine prior exposure to produce long-lasting changes that alter the effects of acute THC administration suggests that chronic nicotine may induce neuroplastic changes that influence the subsequent response to novel THC exposure.