Gary L. Grunewald, Ph.D.
Class of 2006
Gary L. Grunewald
Gary L. Grunewald, Ph.D. is a Professor of Medicinal Chemistry
at the University of Kansas. He obtained undergraduate degrees in both chemistry
and pharmacy at Washington State University where he was elected to membership
in Phi Beta Kappa. He received a Wisconsin Alumni Research Foundation Fellowship
and an NIH Predoctoral Fellowship for his graduate work at the University of
Wisconsin. His Ph.D. dissertation (with Howard Zimmerman) described the chemistry
of barrelene and included the photochemical conversion of barrelene to semibullvalene,
the first recognized example of the di-p-methane rearrangement. He then joined
(1966) the faculty at the University of Kansas in the Department of Medicinal
Chemistry where he has been ever since. He served as department chair in 1994-2003.
He received the Higuchi/Simons Research Achievement Award for research excellence
in the biomedical sciences at the University of Kansas. His research has concentrated
on mechanistic studies of neurotransmitters and drugs affecting them in the
central nervous system employing most of the techniques of drug design (conformationally
defined (rigid) analogs, QSAR, molecular modeling, site-directed mutagenesis
and structure-based drug design using protein crystallography). He has had the
good fortune of working with a number of excellent senior collaborators and
with a wonderful group of undergraduate, graduate and postdoctoral students.
In studies of conformation-activity relationships his group showed that that
amphetamine had one optimal conformation for inhibition of the reuptake of catecholamine
neurotransmitters but had a different optimal conformation for causing vesicular
release of the same neurotransmitter in presynaptic neurons. His group was able
to explain why homozimeldine retained the selectivity for the serotonin transporter
over the norepinephrine transporter that its parent zimeldine displayed and
also explained, through molecular mechanics calculations, why homozimeldine
was less potent than the parent zimeldine. Recent work has concentrated on finding
a potent and selective inhibitor of epinephrine biosynthesis to explore the
poorly understood role of epinephrine in the central nervous system. Through
use of rigid analogs they showed that phenylethylamines bind to the enzyme in
a fully extended conformation and they confirmed the reality of this conclusion
using transferred nuclear Overhauser enhancements to determine the torsion angles
of the flexible ligand 3,4-dichloroamphetamine when bound to the enzyme. They
have shown that a careful combination of steric factors and pKa control using
b-fluorination (an example of the Goldilocks Effect) can result in a potent
inhibitor of phenylethanolamine N-methyltransferase that shows extremely low
affinity for the competing binding site, the a2-adrenoceptor. Through
a combination of nmr studies and quantum chemical calculations, they were able
to accurately predict the relative stereochemistry of six of the seven chiral
centers in epothilone before the x-ray crystal structure of this anticancer
drug was known.
He has served the Medicinal Chemistry Division of ACS as a member of the Long
Range Planning Committee (1991-1994), as Vice Chair (1993), Chair (1994) and
Councilor (1999-2001). He served as general chair of the 27th National Medicinal
Chemistry Symposium in 2000. He served as Chair of the Research Committee (1983-85)
and as a member of the Board of Directors (1980-1991) of the Kansas Affiliate
of the American Heart Association He also served as Chair of the Medicinal Chemistry
and Pharmacognosy Section of the Academy of Pharmaceutical Sciences (1983) and
as Chair of the Pharmaceutical Sciences Section of the American Association
for the Advancement of Science (1994). He serves on the Editorial Advisory Boards
for Bioorganic and Medicinal Chemistry and Bioorganic and Medicinal Chemistry
Letters. He was elected as a Fellow of both the AAPS (2006) and AAAS (1992).
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