Translation of Novel Serotonin 5-HT7 Agonist Drug Candidates in Rodent Models of Fragile X Syndrome
Abstract
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 criterion(Ki < / = 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2016
- Accession Number
- AD1033259
Entities
People
- Clinton E Canal
- Raymond G. Booth
Organizations
- Northeastern University