Welcome to the Research of Evan Lebois
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My current work is being carried out in the laboratory of Allan Levey and Jim Lah in the Center for Neurodegenerative Disease at Emory University in Atlanta. A good majority of the work is being carried out in close collaboration with Joseph Manns in the Department of Psychology here at Emory. Primary efforts will be devoted to utlizing novel, cutting-edge experimental therapeutics in order to better understand the mechanisms of cognitive decline associated with both healthy aging and disease progression. In order to facilitate this translational effort, we are also collaborating with the Vanderbilt Program in Drug Discovery at Vanderbilt University directed by P. Jeffrey Conn. Director of medicinal chemistry Craig Lindsley will be overseeing synthesis and delivery of experimental therapeutics for the proposed studies. Thus, these current research endeavors represent a fusion of the tremendous Alzheimer’s research resources that Emory has to offer as well as the phenomenal community of learning and memory investigators who reside here.
(Above Left: ribbon diagram depicting a potential binding mode of M1 agonist scaffold VU0184670 docked into the a homology model of the M1 receptor, as modeled by Eric Dawson; Above Right: addition of space-filled electrical potentials of adjacent side-chain residues to depict the sterically-occluded nature of this potential binding pocket)
2007-2010
I began my PhD training in pharmacology at Vanderbilt University in Nashville, TN in the laboratories of Craig Lindsley and Jeff Conn working with the Vanderbilt Program in Drug Discovery. During my time here I was involved in several discovery projects, but the bulk of the work I performed comprised developing the first generation of completely selective M1 muscarinic acetylcholine receptor (mAChR) agonists. These compounds possess very attractive physiochemical properties, are readily centrally-penetrant and have demonstrated behavioral efficacy (Lebois, et al. 2010). Perhaps most notably, the M1 receptor has received considerable attention as a drug target due to knockout studies performed in mice, where animals lacking the M1 receptor were deficient in measures of hippocampal learning as well as the induction of hippocampal LTP.
(Above Left: lead optimization scheme developed to synthesize a novel generation of M1 subtype-selective agonists; Above Right: Functional selectivity profile of novel M1 agonists typified. Selectivity is shown versus M2-M5 as measured by a fluorescence-based assay designed to measure an increase in intracellular calcium concentration in cells stably expressing the M1 receptor)
As such, pharmacological activation of the M1 receptor has received much attention over the years as a pro-cognitive strategy to treat central nervous system disorders, culminating in phase III clinical trials for compounds such as Xanomeline (a dual M1/M4 agonist) which showed cognitive efficacy in Schizophrenia and Alzheimer’s patients. While encouraging, the results of M1 discovery programs such as Xanomeline have failed to bear any fruit in terms of FDA approval over the past decades due to the classical problem of encountering dose-limiting side effects. The muscarinic receptors represent a family of five highly conserved family A GPCR drug targets (M1– M5). As such, it has been extraordinarily difficult to devleop subtype-selective ligands for these receptors.
(Table from a recent Eur. J. Pharm. paper illustrating the dearth of M1-selective agonists in existence)
While activating M1 may indeed be pro-cognitive, activating other subtypes – particularly M3 – in the periphery leads to severe dose-limiting SLUD (salivation, lacrimation, urination and defecation) side effects associated with nonselective cholinergic agonists. While at Vanderiblt, I worked as a medicinal chemist and molecular pharmacologist in order to devleop and characterize these novel experimental agonists for the M1 receptor. Outside of medicinal chemistry and molecular pharmacology, my work at Vanderbilt also included performing behavioral pharmacology, slice electrophysiology, nuclear imaging work (PET/SPECT) and collaboration with colleagues in drug metabolism and pharmacokinetics (DMPK) to help drive ligand development.
In mammals, the hippocampus is a brain region that is of paramount importance for learning and memory, underlying episodic memory formation in order to construct a sense of self-awareness in a temporally-graded fashion that can be further modified and updated by external environmental stimuli. Since the hippocampus is subservient to such a critical role in neural function, there are various devastating diseases in which the hippocampus is intimately involved, most notably Alzheimer’s Disease (AD) (Video of Allan Levey giving an overview of AD and ongoing efforts underway at Emory) and dementia, as well as clinical disorders like Post-Traumatic Stress Disorder. AD is one of the single greatest unmet medical needs today, with over 50% of people over the age of 85 showing disease symptoms and no currently FDA-approved treatments that halt disease progression. Thus, the need to both develop safe, effective therapies is extremely great.
Mice that lack the gene coding for the M1 muscarinic acetylcholine receptor (mAChR) in the central nervous system show cognitive impairments consistent with deficits observed in individuals with AD. Additionally, M1 agonists have been demonstrated to be disease modifying with regard to AD neuropathology, promoting soluble amyloid precursor protein processing and reducing amyloid beta plaque burden. Furthermore, the acetylcholinesterase inhibitor Donepezil has been demonstrated to slow the progression from mild cognitive impairment (MCI) to AD in the ApoE4+ subset of MCI patients. Thus, drug candidates that activate mAChRs in the CNS have received much attention for AD therapy, with the M1/M4 agonist Xanomeline showing cognitive efficacy in phase III clinical trials despite failing to be approved by the Food and Drug Administration (FDA) due to dose-limiting side effects. To this end, the goal of my work at Emory is to make use of recently developed subtype-selective mAChR activators in order to activate the brain’s cholinergic circuitry in a such a way as to promote healthy hippocampal processing throughout the normal aging process. This work will also yield valuable molecular insight into how individual subtypes of muscarinic receptors contribute to both spatial memory formation and hippocampal coding of episodic memory in general.
If one wishes to understand the complex mechanisms of AD pathology and effectively intervene therapeutically, one first needs to understand the mechanisms of the normal aging process and how cognition declinces with aging – particularly with regard to how hippocampal function degrades with aging. Since the hippocampus contains a particularly high density of mAChRs, selective muscarinic activators are ideal research tools to probe molecular mechanisms of hippocampal dysfunction with aging. As rats age, it has been shown that the ability of their hippocampus to distinguish novel contexts becomes “rigid,” while those of young rats when switched from familiar environments to novel environments can rapidly encode this change in order to recognize that they are in a new context.
The rats for these studies are to be surgically implanted with a high-density multielectrode recording array containing 32 tetrodes targeted at the hippocampus in order to simultaneously record hippocampal neuronal activity while the rats are freely awake performing various behavioral tasks with the end goal of analyzing neuronal spiking and network synchrony. Since the neurocircuitry of the hippocampus is conserved across the mammalian taxon, these studies will yield precious insight into the molecular basis of hippocampal dysfunction in normal aging. By selective pharmacological intervention in aged rats, we hope to restore the ability to encode novelty to the aged hippocampus. Thus, this work has significant therapeutic relevance to not only Alzheimer’s Disease, but to the cognitive decline that accompanies the physiological aging process at large.
(Below Left: a recording device from the Manns Lab with 32 independently adjustable tetrodes housed inside 32 microdrivers that we use to record neural activity while the rats are freely moving around. This device is permanently surgically implanted to the rat skull prior to testing where the tetrodes are lowered to the brain region of interest through the base collector cannula that sits over a craniotomy window. Below Right: a schematic depicting the basic elements that comprise the 32 tetrode-containing microdrive recording device used in the Manns lab. Note that the 32 tetrodes are funneled into one or more base collector cannula that ultimately sit on top of the skull in a craniotomy window over the brain region of interest that the tetrodes will subsequently be lowered down into in order to record spiking activity. In order to stream the neural data to computers located in the recording room, each of the 32 tetrodes is wired to an interface chip whereby cables attached to a commutator are plugged into each of the four heads on the chip.)
10. Digby, G.J., Bubser, M., Utley, T., Walker, A.G., Lebois, E.P., Noetzel, M.J., Xiang, Z., Sheffler, D.J., Niswender, C.M., Plumley, H.C., Davis, A.A., Morrison, R., Jones, C.K., Daniels, S., Olive, M.F., Lindsley, Nature Neurosci., 2011 (submitted).
9. Evan P. Lebois, Douglas J. Sheffler, Gregory J. Digby, Bruce J. Melancon, James C. Tarr, Hyekyung P. Cho, Ryan Morrison, J. Scott Daniels, Thomas M. Bridges, Zixiu Xiang, Michael R. Wood, P. Jeffrey Conn, Craig W. Lindsley. Development of a Highly Selective, Orally Bioavailable and CNS Penetrant M1 Agonist Derived from the MLPCN Probe, ML071. Bioorg. Med. Chem. Lett., 2011 (in press).
6. Evan P Lebois, Thomas M Bridges, L.Michelle Lewis, Eric S Dawson, Alexander S Kane, Zixiu Xiang, Satyawan B Jadhav, Huiyong Yin, JPhillip Kennedy, Jens Meiler, Colleen M Niswender, Carrie K Jones, P Jeffrey Conn, C David Weaver, Craig W Lindsley. Discovery and Characterization of Novel Subtype-Selective Allosteric Agonists for the Investigation of M1 Receptor Function in the Central Nervous System. ACS Chemical Neuroscience, 10.1021/cn900003h, 1(2), 104-121, 2010.
2. Lebois, EP. Neither typical nor atypical: LY404039 provides proof of concept that selective targeting of mGluR2/3 receptors is a valid mechanism for obtaining antipsychotic efficacy. Curr Top Med Chem, 8(16), 1480-1, 2008.
* = Denotes Co-First Author
1. Lindsley, C.W.; Conn, J.P.; Weaver, C.D.; Niswender, C.M.; Lebois, E.P.; Bridges, T.M. ‘Amidobipiperidinecarboxylate M1 allosteric agonists, analogs and derivatives thereof, and methods of making and using same’ WO 096703, 2010.
2. Lindsley, C.W.; Conn, J.P.; Wood, M.R.; Gogliotti, R.D.; Niswender, C.M.; Melancon, B.J.; Lebois, E.P. ‘Alkyl 3-((2-amidoethyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate analogs as selective M1 agonists and methods of making and using same’ WO 087812, 2011.
3. Lindsley, C.W.; Conn, J.P.; Niswender, C.M.; Wood, M.R.; Chauder, B.A.; Lebois, E.P. ‘Heterocyclyl-azabicyclo[3.2.1]octane analogs as selective M1 agonists and methods of making and using same’ WO 112825, 2011.
2007-Present
M1 mAChR Work
'First Compound for Receptors in Alzheimer's and Schizophrenia Holds Promise'
http://www.sciencedaily.com/releases/2009/04/090420141157.htm
http://www.physorg.com/news159452703.html
2003-2007
Sigma Xi Outstanding Undergraduate Thesis Award
http://www.udel.edu/PR/UDaily/2007/may/theses052407.html
Platform Presentation at 2007 Experimental Biology Meeting in Washington DC
January 2009 - ASPET Graduate Student Travel Award EB2009
July 2008 - July 2010 - Predoctoral Training Grant in Pharmacological Sciences, NIH #5T326M007628-30
June 2007 - August 2007 - Imperial College London Summer Undergraduate Research Studentship
Mentor: Kurt Drickamer
May 2007 - Sigma Xi Outstanding Undergraduate Thesis Award
October 2006 - 2nd Place, University of Maryland Chemical and Biological Sciences Research Symposium
May 2006 - August 2006 - HHMI Undergraduate Research Fellowship
May 2005 - August 2005 - Charles Peter White Undergraduate Research Fellowship
May 2004 - August 2004 - University of Delaware Summer Undergraduate Research Fellowship
General
Chemistry
Neuroscience
Pharmacology
General Biology
(In addition to science, one of the many things I enjoy is ultrarunning. Shown above is a picture from the finish line of my latest adventure in October 2010 where I ran the Grindstone 100 in Shenandoah, VA. That's me on the left and my brother Ryan on the right who generously paced me for 33 miles)
e-mail me at evan.p.lebois@emory.edu