The ␣7 nicotinic acetylcholine receptors (nAChRs) are uniquely sensitive to selective positive allosteric modulators (PAMs), which increase the efficiency of channel activation to a level greater than that of other nAChRs. Although PAMs must work in concert with "orthosteric" agonists, compounds such as GAT107 ((3aR,4S,9bS)-4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) have the combined properties of agonists and PAMs (ago-PAM) and produce very effective channel activation (direct allosteric activation (DAA)) by operating at two distinct sites in the absence of added agonist. One site is likely to be the same transmembrane site where PAMs like PNU-120596 function. We show that the other site, required for direct activation, is likely to be solventaccessible at the extracellular domain vestibule. We identify key attributes of molecules in this family that are able to act at the DAA site through variation at the aryl ring substituent of the tetrahydroquinoline ring system and with two different classes of competitive antagonists of DAA. Analyses of molecular features of effective allosteric agonists allow us to propose a binding model for the DAA site, featuring a largely non-polar pocket accessed from the extracellular vestibule with an important role for Asp-101. This hypothesis is supported with data from sitedirected mutants. Future refinement of the model and the characterization of specific GAT107 analogs will allow us to define critical structural elements that can be mapped onto the receptor surface for an improved understanding of this novel way to target ␣7 nAChR therapeutically.The ␣7 nicotinic acetylcholine receptor (nAChR) 3 is a recognized target for both central nervous system disorders, such as Alzheimer disease and schizophrenia, and peripheral indications, such as inflammation and associated pain (1, 2). As with other nicotinic receptors, conventional thinking has focused on the function of ␣7 as a ligand-gated ion channel that is activated by the transmitter acetylcholine (ACh). However, this traditional perspective has been challenged and enlarged upon by numerous observations. First, ␣7 receptors can be activated by choline as well as ACh (3), removing it from the position of being strictly optimized for synaptic function and suggesting that it may respond to tissue factors, especially in the context of playing a role in the modulation of inflammation (4). Additional insights have come from the exploration of the rich pharmacology of this receptor, beginning with the identification of a variety of selective agonists and partial agonists that control the conformational dynamics of activation and desensitization in ways that are totally unlike the behavior of other nAChRs, such as those of the neuromuscular junction and autonomic ganglia that are clearly optimized for fast synaptic transmission (1, 5). To a large degree, the specializations of synaptic nAChR arise from the evolution of different types of subunits that create the ACh-binding site at the interfa...

An improved, safe, and scalable isolation process for (substituted) pyridine and quinoline N-oxides in quantitative yields along with high purities using the m-CPBA–NH3(g) system is described. The safety was assessed by reaction calorimetry and differential scanning calorimetry studies for possible hazards during the conversion and isolation steps. Careful interpretation of the data substantiated the safety and scalability. The process flow is simplified to meet the industrial requirements of safety, cost-effectiveness, and utility minimization. The reaction was safely demonstrated at a 2.5 kg scale.

A highly efficient and improved synthetic methodology for the preparation of 3,4-dihydropyrimidin-2(1H)-one derivatives in good to excellent yield via Biginelli reaction of β-ketoesters/β-diketone, urea/thiourea and various aldehydes using new, efficient and recyclable sulfated polyborate catalyst under the solvent-free condition is reported.

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