Search

Recent findings indicate that selective activation of the M4 muscarinic acetylcholine receptor (M4 mAChR) may represent a novel treatment approach for the psychotic symptoms and cognitive disturbances observed in several neuropsychiatric disorders. In the present studies, cognitive performance of M4 mAChR knock-out mice (M4-KO mice) was examined across a series of computer touchscreen-based pairwise discrimination tasks assessing susceptibility to interference from previously learned competing sets of information. While M4-KO mice acquired the initial discrimination task in a similar number of sessions as wildtype mice, the M4-KO mice showed impaired acquisition on all subsequent visual discriminations. In addition, the novel M4 positive allosteric modulator VU0467154 reversed disruptions in pairwise discrimination induced by MK-801, an antagonist of the N-methyl-D-aspartate subtype of glutamate receptors. These data reveal that selective M4 mAChR activation is critical for modulation of normal associativ...

The αvβ3 integrin receptor ligand [125I]L-775,219, 1c, was synthesized for use in an in vitro receptor binding assay with high specific activity (>1500 Ci/mmol) and a radiochemical yield of 15–20%. Conversion of iodide 1b to the corresponding aryl trimethylstannane 2, followed by radioiodination using Na125I/iodobead gave 1c. Copyright © 2001 John Wiley & Sons, Ltd.

The synthesis of [ 3 H]L-734,217, 1b, an orally active fibrinogen receptor antagonist, is described. The conversion of 3-amino crotonate 6 to [ 3 H]L-734,217 was carried out via a two step sequence of catalytic tritiation followed by basic hydrolysis. Deuterium model reactions showed that the reduction of 6 with PtO2 occurred via hydrogen transfer from the solvent (ethanol or acetic acid) leading to poor isotope incorporation. When this reduction was conducted in methanol with 10% Pd/C, good isotope incorporation resulted. Ultimately, [ 3 H]L-734,217 was formed with a specific activity of 42 Ci/mmol.

Potent, novel 7-oxo alpha(v)beta3 antagonists have been prepared. These antagonists offer decreased plasma protein binding and excellent pharmacokinetic profiles.