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Biochemical and behavioral studies of the 5‐HT1B receptor agonist, CP‐94,253
CP‐94,253, 3‐(1,2,5,6‐tetrahydro‐4‐pyridyl)‐5‐propoxypyrrolo[3,2‐b]pyridine, a new serotonergic ligand, was found to exhibit significantly greater binding affinity at 5‐HT1B receptors than at 5‐HT1AExpand
The 5-HT3 antagonist tropisetron (ICS 205-930) is a potent and selective alpha7 nicotinic receptor partial agonist.
The 5-HT3 receptor antagonist tropisetron (ICS 205-930) was found to be a potent and selective partial agonist at alpha7 nicotinic receptors. Two other 5-HT3 receptor antagonists, ondansetron andExpand
Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase Inhibitor.
Compound 4 is a potent inhibitor of γ-secretase, demonstrating a 193-fold selectivity against Notch, and significantly reduced Aβ40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs. Expand
The Amyloid-β Rise and γ-Secretase Inhibitor Potency Depend on the Level of Substrate Expression*
It is shown that the Aβ rise depends on the β-secretase-derived C-terminal fragment of APP (βCTF or C99 levels with low levels with high levels causing rises, while the N-terminally truncated form of Aβ, known as “p3,” formed by α- secretase cleavage, did not exhibit a rise. Expand
(-)-Spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one], a conformationally restricted analogue of acetylcholine, is a highly selective full agonist at the alpha 7 nicotinic acetylcholine
Preliminary SAR of AR-R17779 presented here indicate that there is little scope for modification of this rigid molecule as even minor changes result in significant loss of the alpha 7 nicotinic receptor affinity. Expand
The in vivo pharmacological profile of a 5‐HT1 receptor agonist, CP‐122, 288, a selective inhibitor of neurogenic inflammation
It is demonstrated that in the rat, CP‐122, 288 is a highly potent and selective inhibitor of neurogenic inflammation in intracranial tissues, at doses which are devoid of vasoconstrictor activity in dog and in the anaesthetized dog. Expand
3-(1,2,5,6-Tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one: a potent and selective serotonin (5-HT1B) agonist and rotationally restricted phenolic analogue of
2 appears to lie in the ability of a pyrrolo[3,2-b]pyrid-5-one to act as a rotationally restricted bioisosteric replacement for 5-hydroxyindole, which is shown to be biochemically discriminatory in its ability to selectively inhibit forskolin-stimulated adenylate cyclase activity only at the 5-HT1B receptor. Expand
Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer's Mouse Phenotypes.
Metabotropic glutamate receptor 5 (mGluR5) has been implicated in Alzheimer's disease (AD) pathology. We sought to understand whether mGluR5's role in AD requires glutamate signaling. We used aExpand
Discovery of (R)-4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide (BMS-694153): a
Compound 4 has good intranasal bioavailability in rabbits and shows dose-dependent activity in validated in vivo and ex vivo migraine models and is described as a molecule with outstanding potency, a favorable predictive toxicology profile, and remarkable aqueous solubility. Expand
Acyl guanidine inhibitors of β-secretase (BACE-1): optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis.
Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma A β levels, but poor brain exposure was observed, and significant reductions in brain Aβ levels were not obtained. Expand