- Design, Synthesis, and Structure-Activity Relationship Studies of (4-Alkoxyphenyl)glycinamides and Bioisosteric 1,3,4-Oxadiazoles as GPR88 Agonists
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Increasing evidence implicates the orphan G protein-coupled receptor 88 (GPR88) in a number of striatal-associated disorders. In this study, we report the design and synthesis of a series of novel (4-alkoxyphenyl)glycinamides (e.g., 31) and the corresponding 1,3,4-oxadiazole bioisosteres derived from the 2-AMPP scaffold (1) as GPR88 agonists. The 5-amino-1,3,4-oxadiazole derivatives (84, 88-90) had significantly improved potency and lower lipophilicity compared to 2-AMPP. Compound 84 had an EC50 of 59 nM in the GPR88 overexpressing cell-based cAMP assay. In addition, 84 had an EC50 of 942 nM in the [35S]GTPγS binding assay using mouse striatal membranes but was inactive in membranes from GPR88 knockout mice, even at a concentration of 100 μM. In vivo pharmacokinetic testing of 90 in rats revealed that the 5-amino-1,3,4-oxadiazole analogues may have limited brain permeability. Taken together, these results provide the basis for further optimization to develop a suitable agonist to probe GPR88 functions in the brain.
- Rahman, Md Toufiqur,Decker, Ann M.,Langston, Tiffany L.,Mathews, Kelly M.,Laudermilk, Lucas,Maitra, Rangan,Ma, Weiya,Darcq, Emmanuel,Kieffer, Brigitte L.,Jin, Chunyang
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p. 14989 - 15012
(2020/11/30)
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- Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
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The present invention provides compounds useful, for example, for modulating insulin levels in a subject and that have the general formula [in-line-formulae]Q-L1-P-L2-M-X-L3-A [/in-line-formulae] wherein the definitions of
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Page/Page column 53
(2010/02/15)
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- Design and synthesis of dual inhibitors of acetylcholinesterase and serotonin transporter targeting potential agents for Alzheimer's disease.
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Highly efficient acetylcholinesterase (AChE) and serotonin transporter (SERT) dual inhibitors, (S)-4 and (R)-13 were designed and synthesized on the basis of the hypothetical model of AChE active site. Both compounds showed potent inhibitory activities against AChE and SERT. [structure: see text]
- Kogen, Hiroshi,Toda, Narihiro,Tago, Keiko,Marumoto, Shinji,Takami, Kazuko,Ori, Mayuko,Yamada, Naho,Koyama, Kazuo,Naruto, Shunji,Abe, Kazumi,Yamazaki, Reina,Hara, Takao,Aoyagi, Atsushi,Abe, Yasuyuki,Kaneko, Tsugio
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p. 3359 - 3362
(2007/10/03)
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