Design, synthesis, and evaluation of substituted alkylindoles that activate G protein-coupled receptors distinct from the cannabinoid CB and CB receptors.

The alkylindole (AI), WIN55212-2, modulates the activity of several proteins, including cannabinoid receptors 1 and 2 (CBR, CBR), and at least additional G protein-coupled receptor (GPCR) that remains uncharacterized with respect to its molecular identity and pharmacological profile. Evidence suggests that such AI-sensitive GPCRs are expressed by the human kidney cell line HEK293. We synthesized fourteen novel AI analogues and evaluated their activities at AI-sensitive GPCRs using [S]GTPγS and [H]WIN55212-2 binding in HEK293 cell membranes, and performed in silico pharmacophore modeling to identify characteristics that favor binding to AI-sensitive GPCRs versus CBR/CBR.

Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome.

Human congenital central hypoventilation syndrome (CCHS), resulting from mutations in transcription factor PHOX2B, manifests with impaired responses to hypoxemia and hypercapnia especially during sleep. To identify brainstem structures developmentally affected in CCHS, we analyzed two postmortem neonatal-lethal cases with confirmed polyalanine repeat expansion (PARM) or Non-PARM (PHOX2B∆8) mutation of PHOX2B. Both human cases showed neuronal losses within the locus coeruleus (LC), which is important for central noradrenergic signaling.

A robust method to derive functional neural crest cells from human pluripotent stem cells.

Neural crest (NC) cells contribute to the development of many complex tissues of all three germ layers during embryogenesis, and its abnormal development accounts for several congenital birth defects. Generating NC cells-including specific subpopulations such as cranial, cardiac, and trunk NC cells-from human pluripotent stem cells will provide a valuable model system to study human development and disease. Here, we describe a rapid and robust NC differentiation method called "LSB-short" that is based on dual SMAD pathway inhibition.

Binding of NIR-conPK and NIR-6T to astrocytomas and microglial cells: evidence for a protein related to TSPO.

PK 11195 and DAA1106 bind with high-affinity to the translocator protein (TSPO, formerly known as the peripheral benzodiazepine receptor). TSPO expression in glial cells increases in response to cytokines and pathological stimuli. Accordingly, [(11)C]-PK 11195 and [(11)C]-DAA1106 are recognized molecular imaging (MI) agents capable of monitoring changes in TSPO expression occurring in vivo and in response to various neuropathologies.

The therapeutic potential of novel cannabinoid receptors.

Cannabinoids produce a plethora of biological effects, including the modulation of neuronal activity through the activation of CB(1) receptors and of immune responses through the activation of CB(2) receptors. The selective targeting of either of these two receptor subtypes has clear therapeutic value. Recent evidence indicates that some of the cannabinomimetic effects previously thought to be produced through CB(1) and/or CB(2) receptors, be they on neuronal activity, on the vasculature tone or immune responses, still persist despite the pharmacological blockade or genetic ablation of CB(1) and/or CB(2) receptors.