Evan P. Lebois
Graduate Student
B.S. with distinction, Biochemistry, University of Delaware, 2007
B.S. with distinction, Biology: Cellular/Molecular Biology/
Genetic Concentration, University of Delaware, 2007
Phone: (615) 322-8622
Fax: (615) 322-8577
Email: evan.p.lebois@vanderbilt.edu
Location: 12475 MRB IV (Langford)
Biosketch and Research Interests
Evan Lebois, B.S. is a Pharmacology graduate student who joined the Conn and Lindsley laboratories in May 2008. Evan spent his previous life at the University of Delaware where he worked under the mentorship of Erica Selva for the better part of three and a half years conducting molecular genetics research using Drosophila melanogaster as a model organism to probe questions of glycosylation in a developmental context. Following this, Evan spent his senior summer working abroad at Imperial College in London, England under the mentorship of Kurt Drickamer in the molecular biosciences department characterizing human lectins and learning more glycobiology.
Evan’s research at Vanderbilt focuses on the utilization of medicinal chemistry, coupled with in vitro and in vivo pharmacology, to aid in the design and optimization of novel allosteric agonists and allosteric antagonists of the M1 muscarinic acetylcholine receptor (mAchR). The M1 receptor is implicated as a central player in the manifestation of various neuropathophysiologies including Alzheimer’s disease, schizophrenia and Dystonia. Due to significant evolutionary conservation across the orthosteric site of the five muscarinic subtypes (M1-M5), traditional drug discovery programs aimed at developing orthosterically-acting compounds have failed largely due to an inability of achieving subtype selectivity. This failure to achieve subtype selectivity results in a host of unwanted side effects, including severe GI and Parkinsonian effects. Compounds such as Xanomeline have shown proof of concept that targeting the M1 receptor for the treatment of cognitive decline associated with AD and the negative/cognitive symptoms associated with schizophrenia presents a clinically efficacious means of therapy.
Furthermore, the striatal cholinergic hypertone present in patients with Dystonia provides the perfect opportunity for selectively-acting M1 antagonists as a way to post-synaptically compensate for this Ach hypertone via the M1-containing striatal efferents. The approach taken by Evan seeks to take advantage of less-conserved allosteric sites present on the receptors in order to achieve subtype selectivity and sidestep unwanted side effects. By utilizing these allosteric sites, truly selective M1 allosteric agonists can potentially be developed for the therapy of Alzheimer’s and schizophrenia and selective M1 allosteric antagonists can be developed as a frontline therapy for Dystonia.
Selected Publications
Evan P. Lebois. Neither typical nor atypical: LY404039 provides proof of concept that selective targeting of mGluR2/3 receptors is a valid in vivo mechanism for antipsychotic efficacy. Curr. Top. Med. Chem., 2008 (submitted).
Lewis, J., Lebois, E.P., Lindsley, C.W. Allosteric modulators of kinases and GPCRs. Design principles and structural diversity. Curr. Opin. Chem. Biol., 12, 269-280, 2008 (invited).
R. Nathan Daniels, Kwangho Kim, Evan P. Lebois, Hubert Muchalski, Mary Hughes and Craig W. Lindsley. Microwave-assisted protocols for the expedited synthesis of pyrazolo[1,5-a] and [3,4-d]pyrimidines. Tetrahedron Lett., 49(2), 305-310, 2008.
Colleen M. Niswender*, Evan P. Lebois*, Cherry Luo, Kari A. Myers-Johnson, Kwangho Kim, Hubert Muchalski, Huiyong Yin, P. Jeffrey Conn, and Craig W. Linsley (*= co-author). Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4): Part I. Discovery of pyrazolo[3,4-b]pyrimidines as novel mGluR4 positive allosteric modulators. Bioorg. Med. Chem. Lett., 18, 5626-5630, 2008.
Leslie N. Aldrich*, Evan P. Lebois*, L. Michelle Lewis, Natalia T. Nalywajko, Colleen M. Niswender, C. David Weaver, P. Jeffrey Conn, Craig W. Lindsley (*= co-author). MAOS protocols for the general synthesis and lead optimization of 3,6-disubstituted-[1,2,4]triazolo[4,3-b]pyridazines. Tet. Lett., 50, 212-215, 2009.
