TY - JOUR
T1 - Modulating the Serotonin Receptor Spectrum of Pulicatin Natural Products
AU - Lin, Zhenjian
AU - Smith, Misty D.
AU - Concepcion, Gisela P.
AU - Haygood, Margo G.
AU - Olivera, Baldomero M.
AU - Light, Alan
AU - Schmidt, Eric W.
N1 - Funding Information:
This research was supported by NIH R01GM107557 and Fogarty International Center of the National Institutes of Health under Award No. U19TW008163. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Chemical resources reported in this work were created at the University of Utah. Serotonin receptor screening and functional analysis were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract No. HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is directed by B. L. Roth M.D., Ph.D., at the University of North Carolina at Chapel Hill, NC, and Project Officer J. Driscoll at NIMH, Bethesda, MD, USA. We thank the NIH/NINDS Epilepsy Therapy Screening Program (ETSP) for the epilepsy model testing performed.
Publisher Copyright:
© 2017 The American Chemical Society and American Society of Pharmacognosy.
PY - 2017/8/25
Y1 - 2017/8/25
N2 - Serotonin (5-HT) receptors are important in health and disease, but the existence of 14 subtypes necessitates selective ligands. Previously, the pulicatins were identified as ligands that specifically bound to the subtype 5-HT2B in the 500 nM to 10 μM range and that exhibited in vitro effects on cultured mouse neurons. Here, we examined the structure-activity relationship of 30 synthetic and natural pulicatin derivatives using binding, receptor functionality, and in vivo assays. The results reveal the 2-arylthiazoline scaffold as a tunable serotonin receptor-targeting pharmacophore. Tests in mice show potential antiseizure and antinociceptive activities at high doses without motor impairment.
AB - Serotonin (5-HT) receptors are important in health and disease, but the existence of 14 subtypes necessitates selective ligands. Previously, the pulicatins were identified as ligands that specifically bound to the subtype 5-HT2B in the 500 nM to 10 μM range and that exhibited in vitro effects on cultured mouse neurons. Here, we examined the structure-activity relationship of 30 synthetic and natural pulicatin derivatives using binding, receptor functionality, and in vivo assays. The results reveal the 2-arylthiazoline scaffold as a tunable serotonin receptor-targeting pharmacophore. Tests in mice show potential antiseizure and antinociceptive activities at high doses without motor impairment.
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U2 - 10.1021/acs.jnatprod.7b00317
DO - 10.1021/acs.jnatprod.7b00317
M3 - Article
C2 - 28745513
AN - SCOPUS:85028334040
SN - 0163-3864
VL - 80
SP - 2360
EP - 2370
JO - Journal of Natural Products
JF - Journal of Natural Products
IS - 8
ER -