N)-Methanocarba ([3.1.0]bicyclohexyl) adenosines and corresponding ribosides were synthesized to identify novel A 1 adenosine receptor (A 1 AR) agonists for CNS or peripheral applications. Human and mouse AR binding was determined to assess the constrained ring system's A 1 AR compatibility. N 6 -Dicyclobutylmethyl ribose agonist (9, MRS7469, >2000-fold selective for A 1 AR) and known truncated N 6 -dicyclopropylmethyl methanocarba 7 (MRS5474) were drug-like.The pure diastereoisomer of known riboside 4 displayed high hA 1 AR selectivity. Methanocarba modification reduced A 1 AR selectivity of N 6 -dicyclopropylmethyl and endo-norbornyladenosines, but increased ribavirin selectivity. Most analogues tested (ip.) were inactive or weak in inducing mouse hypothermia, despite mA 1 AR full agonism and variable mA 3 AR efficacy, but

A genetic polymorphism within the gene encoding the pituitary adenylate cyclase- activating polypeptide (PACAP) receptor type I (PAC1R) has recently been associated with hyper-reactivity to threat-related cues in women, but not men, with post-traumatic stress disorder (PTSD). PACAP is a highly conserved peptide, whose role in mediating adaptive physiological stress responses is well established. Far less is understood about the contribution of PACAP signaling in emotional learning and memory, particularly the encoding of fear to discrete cues. Moreover, a neurobiological substrate that may account for the observed link between PAC1R and PTSD in women, but not men, has yet to be identified. Sex differences in PACAP signaling during emotional learning could provide novel targets for the treatment of PTSD. Here we investigated the contribution of PAC1R signaling within the prefrontal cortex to the acquisition of cued fear in female and male rats. We used a variant of fear conditioning called trace fear conditioning, which requires sustained attention to fear cues and depends on working-memory like neuronal activity within the prefrontal cortex. We found that cued fear learning, but not spatial working memory, was impaired by administration of a PAC1R antagonist directly into the prelimbic area of the prefrontal cortex. This effect was specific to females. We also found that levels of mRNA for the PAC1R receptor in the prelimbic cortex were greater in females compared with males, and were highest during and immediately following the proestrus stage of the estrous cycle. Together, these results demonstrate a sex-specific role of PAC1R signaling in learning about threat-related cues.

The A 3 adenosine receptor (A 3 AR) is a promising therapeutic target for inflammatory diseases, cancer, and chronic neuropathic pain, with agonists already in advanced clinical trials. Here we report an in-depth comparison of the pharmacological properties and structure−activity relationships of existing and expanded compound libraries of 2-substituted 1H-imidazo[4,5-c]quinolin-4-amine and 4-amino-substituted quinoline derivatives that function as A 3 AR positive allosteric modulators (PAMs). We also show that our lead compound from each series enhances adenosine-induced A 3 AR signaling preferentially toward activation of Gα i3 and Gα oA isoproteins, which are coexpressed with the A 3 AR in immune cells and spinal cord neurons. Finally, utilizing an extracellular/intracellular chimeric A 3 AR approach composed of sequences from a responding (human) and a nonresponding (mouse) species, we provide evidence in support of the idea that the imidazoquinolin-4-amine class of PAMs variably interacts dually with the orthosteric ligand binding site as well as with a separate allosteric site located within the inner/intracellular regions of the receptor. This study has advanced both structural and pharmacological understanding of these two classes of A 3 AR PAMs, which includes leads for future pharmaceutical development.

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Objective The aim of the study is to assess the correlation of renal regional tissue saturation of oxygen (RrSO2) measured by near-infrared spectroscopy (NIRS) in preterm neonates to venous oxygen saturation (SvO2) obtained from umbilical venous catheters (UVCs), arterial oxygen saturation (SaO2) obtained from umbilical artery catheters (UACs), and capillary oxygen saturation (ScO2) from capillary heel blood draws. Study Design A secondary analysis of a prospective RrSO2 monitoring study in preterm neonates born <32 weeks gestational age. Neonates with any blood gas obtained during RrSO2 monitoring were included. RrSO2 was compared with simultaneous O2 saturation using non-parametric Mann Whitney U-test and Spearman correlation coefficient. Results In 35 neonates, 25 UVC, 151 UAC, and 68 heel capillary specimens were obtained. RrSO2 was lower than the median SvO2 (58.8 vs. 78.9, p <0.01), SaO2 (51.0 vs. 93.2, p <0.01), and ScO2 (62.2 vs. 94.25, p <0.01). RrSO2 values correlated to both SaO2 and ScO2 (r = 0.32; p <0.01, r = 0.26; p = 0.03), but not SvO2 (r = 0.07; p = 0.74). Conclusion In this secondary analysis, RrSO2 was consistently lower than blood gas O2 saturations and correlated with SaO2 and ScO2 but not SvO2. Lack of a correlation to SvO2 could be due to the small UVC sample size limiting statistical power. Future studies should prospectively evaluate if RrSO2 truly primarily reflects venous oxygenation in preterm neonates. Key Points