Novel and selective partial agonists of 5-HT3 receptors. 2. Synthesis and biological evaluation of piperazinopyridopyrrolopyrazines, piperazinopyrroloquinoxalines, and piperazinopyridopyrroloquinoxalines

Journal of Medicinal Chemistry
H PrunierM Hamon

Abstract

In continuation of our previous work on piperazinopyrrolothienopyrazine derivatives, three series of piperazinopyridopyrrolopyrazines, piperazinopyrroloquinoxalines, and piperazinopyridopyrroloquinoxalines were prepared and evaluated as 5-HT3 receptor ligands. The chemical modifications performed within these new series led to structure-activity relationships regarding both high affinity and selectivity for the 5-HT3 receptors that are in agreement with those established previously for the pyrrolothienopyrazine series. The best compound (8a) obtained in these new series is in the picomolar range of affinity for 5-HT3 receptors with a selectivity higher than 10(6). Four of the high-affinity 5-HT3 ligands (8a, 15a,b, and 16d) were selected in both the pyridopyrrolopyrazine and the pyrroloquinoxaline series and were characterized in vitro and in vivo as agonists or partial agonists. Compound 8a was also evaluated in the light/dark test where it showed potential anxiolytic-like activity at very low doses per os.

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Citations

Mar 7, 2001·Bioorganic & Medicinal Chemistry Letters·I BaglinS Rault
Jun 20, 2014·European Journal of Medicinal Chemistry·Nicolas PrimasNadine Azas
Mar 4, 2017·The Journal of Organic Chemistry·Caixia XieChen Ma
Jun 13, 2015·Tobacco Control·Hillel R AlpertGregory N Connolly
Jan 6, 2010·The Journal of Organic Chemistry·Jonathan T ReevesChris H Senanayake
Nov 14, 1997·Journal of Medicinal Chemistry·G CampianiT Mennini
Jul 23, 2002·Journal of Chemical Information and Computer Sciences·Ronan BureauSylvain Rault
May 27, 2014·Journal of Chemical Information and Modeling·Alban LepailleurSylvain Rault
Mar 6, 2009·Bioorganic & Medicinal Chemistry·Stéphane LemaîtreSylvain Rault
Apr 8, 1999·Journal of Chemical Information and Computer Sciences·C DaveuS Rault
Mar 26, 2002·Journal of Chemical Information and Computer Sciences·Ronan BureauSylvain Rault
Oct 26, 2002·The Journal of Organic Chemistry·Byoung Se LeeDae Yoon Chi
Jun 21, 2001·Journal of Chemical Information and Computer Sciences·R BureauS Rault

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