Van Andel Institute researchers co-author blueprint for more selective serotonin receptor activators

Serotonin receptors are drug targets for anxiety, depression obesity and other human diseases

Grand Rapids, Mich. (March 27, 2013) – A pair of international studies co-authored by Van Andel Institute scientists and published online this week in Science provides a blueprint for designing more selective serotonin receptor activators.

The neurotransmitter serotonin or 5-hydroxytryptamine (5-HT) regulates a wide spectrum of human physiology. Receptors for the 5-HT receptor family are distributed throughout the body’s organ systems and serve as drug targets for a number of human diseases including anxiety, depression, migraines and obesity among others.

Current drugs can often bind to multiple serotonin receptors, a challenge for drug developers seeking a more efficient and effective targeting mechanism and the avoidance of certain receptors, which can cause dangerous and unwanted side effects. The new studies provide the atomic crystal structures of 5-HT1B and of 5-HT2B (two of 14 known 5-HT receptor subtypes), each bound to the serotonergic migraine drugs ergotamine and dihydroergotamine.

“These studies provide a comprehensive structural basis for understanding receptor-ligand interactions and designing subtype-selective serotonergic drugs,” said H. Eric Xu, Ph.D., Head of Van Andel Institute’s Center for Structural Biology & Drug Discovery and Distinguished Director of the VARI/SIMM Research Center of the Chinese Academy of Sciences. “Pinpointing these structural features could facilitate the design of safer and more effective medications.”

Dr. Xu is senior author of a study headed by Chong Wang, Yi Jiang and Jinming Ma providing the structure of the 5-HT1B receptor and contributing author to a paper providing the structure of the 5-HT2B receptor, both published on March 21, 2013 in Science Express, the advance online version of the journal Science.

In addition to Dr. Xu and his Van Andel Institute colleagues Jinming Ma, Xiang Gao, Edward X. Zhou, Karsten Melcher and Chenghai Zhang, this international effort included teams headed by Raymond C. Stevens of The Scripps Research Institute, Bryan L. Roth, of the University of North Carolina Chapel Hill Medical School and Hualiang Jiang of the Shanghai Institute of Materia Medica.

“The publication of these structures brings to light aspects of the receptor-ligand relationship previously understood only theoretically,” said Karsten Melcher, Ph.D., Head of Van Andel Institute’s Laboratory of Structural Biology and Biochemistry. “They will provide a more comprehensive blueprint for drug designers.”

This work was supported by the National Institute of General Medical Sciences (PSI:Biology grant U54 GM094618), the National Institutes of Health Common Fund in Structural Biology (P50 GM073197), the Jay and Betty Van Andel Foundation, the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK071662), Chinese Ministry of Science and Technology (grants 2012ZX09301001-005 and 2012CB910403); Amway (China); the National Institute of Mental Health (NIMH) (R01 MH61887, U19 MH82441), the National Institute on Drug Abuse (R01 DA27170) and the NIMH Psychoactive Drug Screening Program.

Read Both Papers at Science Express:

Structural Features for Functional Selectivity at Serotonin Receptors
Structural Basis for Molecular Recognition at Serotonin Receptors 

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About Van Andel Institute

Established by Jay and Betty Van Andel in 1996, Van Andel Institute (VAI) is an independent research and educational organization based in Grand Rapids, Mich., dedicated to preserving, enhancing and expanding the frontiers of medical science, and to achieving excellence in education by probing fundamental issues of education and the learning process.  Van Andel Research Institute (VARI), VAI’s research arm, is dedicated to studying the genetic, cellular and molecular origins of cancer, Parkinson’s and other diseases and working to translate those findings into effective therapies. This is accomplished through the work of more than 200 researchers in on-site laboratories and in collaborative partnerships that span the globe. Find out more about Van Andel Institute or donate by visiting www.vai.org