Translation of Novel Serotonin 5-HT7 Agonist Drug Candidates in Rodent Models of Fragile X Syndrome
Technical Report,15 Aug 2015,14 Sep 2016
Northeastern University Boston United States
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The objective of this grant is to synthesize 5-PAT-type 5HT7 receptor agonists and assess their effectiveness to correct FXS phenotypes in Fmr1-KO mice and other mouse models of FXS symptoms. We completed several objectives as described in the Statement of Work. We successfully synthesized 35 novel 5-PAT analogs, and determined their affinities at the human 5HT7 receptor. Seven compounds including two race mates met 5HT7 affinity potency criterionKi 25 nM for further pharmacological assessment. Five of seven were tested in functional assays, and each was a 5HT7 agonist, as determined by 5HT7-Gs-cAMP signaling in HEK293 cells stably expressing the human 5HT7 receptor the racemates were not tested. All seven compounds were screened for off-target affinity. One compound met criteria for 10-fold 5HT7 selectivity, and scale up synthesis is currently underway to advance this compound for in vivo assessment.
- Medicine and Medical Research