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Metropolitan Government of Nashville-Davidson (balance), TN, United States

Wenthur C.J.,Vanderbilt University | Bennett M.R.,Vanderbilt University | Lindsley C.W.,Vanderbilt University | Lindsley C.W.,Vanderbilt Center for Neuroscience Drug Discovery
ACS Chemical Neuroscience | Year: 2014

Fluoxetine (Prozac) was the first major breakthrough for the treatment of depression since the introduction of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) nearly 30 years earlier. It was the first selective serotonin reuptake inhibitor (SSRI) approved by the United States Food and Drug Administration, offering superior efficacy and reduced side effects relative to TCAs and MAOIs. Though a debate remains regarding the exact mechanism by which the clinical efficacy of fluoxetine is manifested, the importance of fluoxetine and related SSRIs to the field is unquestionable. The trade name Prozac has permeated popular culture, helping to raise awareness of depression and to diminish the prevalence of long-standing stigmas associated with this illness. In this Review, we will showcase the history and importance of fluoxetine to neuroscience in general, as well as for the treatment of depression, and review the synthesis, pharmacology, drug metabolism, and adverse effects of fluoxetine. © 2013 American Chemical Society. Source


Wenthur C.J.,Vanderbilt University | Lindsley C.W.,Vanderbilt University | Lindsley C.W.,Vanderbilt Center for Neuroscience Drug Discovery
ACS Chemical Neuroscience | Year: 2013

Clozapine was the first true breakthrough in schizophrenia treatment since the discovery of chlorpromazine in 1950, effectively treating positive, negative, and some cognitive symptoms, as well as possessing unprecedented efficacy in treatment-resistant patients. Despite over 30 years of intense study, the precise molecular underpinnings that account for clozapine's unique efficacy remain elusive. In this Viewpoint, we will showcase the history and importance of clozapine to neuroscience in general, as well as for the treatment of schizophrenia, and review the synthesis, pharmacology, drug metabolism, and adverse events of clozapine. © 2013 American Chemical Society. Source


Sheffler D.J.,Vanderbilt Center for Neuroscience Drug Discovery | Pinkerton A.B.,Sanford Burnham Institute for Medical Research | Dahl R.,Sanford Burnham Institute for Medical Research | Markou A.,University of California at San Diego | Cosford N.D.P.,Sanford Burnham Institute for Medical Research
ACS Chemical Neuroscience | Year: 2011

Group II metabotropic glutamate (mGlu) receptors consist of the metabotropic glutamate 2 (mGlu2) and metabotropic glutamate 3 (mGlu3) receptor subtypes which modulate glutamate transmission by second messenger activation to negatively regulate the activity of adenylyl cyclase. Excessive accumulation of glutamate in the perisynaptic extracellular region triggers mGlu2 and mGlu3 receptors to inhibit further release of glutamate. There is growing evidence that the modulation of glutamatergic neurotransmission by small molecule modulators of Group II mGlu receptors has significant potential for the treatment of several neuropsychiatric and neurodegenerative diseases. This review provides an overview of recent progress on the synthesis and pharmacological characterization of positive and negative allosteric modulators of the Group II mGlu receptors. © 2011 American Chemical Society. Source


O'Reilly M.C.,Vanderbilt University | Lindsley C.W.,Vanderbilt University | Lindsley C.W.,Vanderbilt Center for Neuroscience Drug Discovery
Tetrahedron Letters | Year: 2012

In this Letter, we describe a novel three-step, one-pot procedure for the enantioselective synthesis of N-benzyl protected morpholines and orthogonally N,N′-protected piperazines with chiral alkyl groups installed at the C2 position of each heterocyclic core via organocatalysis. This methodology allows for the rapid preparation of functionalized morpholines and piperazines that are not readily accessible through any other chemistry in good to excellent % ee (55-98% ee). © 2011 Elsevier Ltd. All rights reserved. Source


Lindsley C.W.,Vanderbilt Center for Neuroscience Drug Discovery
Journal of Medicinal Chemistry | Year: 2014

The identification of sites on receptors topographically distinct from the orthosteric sites, so-called allosteric sites, has heralded novel approaches and modes of pharmacology for target modulation. Over the past 20 years, our understanding of allosteric modulation has grown significantly, and numerous advantages, as well as caveats (e.g., flat structure-activity relationships, species differences, "molecular switches"), have been identified. For multiple receptors and proteins, numerous examples have been described where unprecedented levels of selectivity are achieved along with improved physiochemical properties. While not a panacea, these novel approaches represent exciting opportunities for tool compound development to probe the pharmacology and therapeutic potential of discrete molecular targets, as well as new medicines. In this Perspective, in commemoration of the 2013 Philip S. Portoghese Medicinal Chemistry Lectureship (Lindsley, C. W. Adventures in allosteric drug discovery. Presented at the 246th National Meeting of the American Chemical Society, Indianapolis, IN, September 10, 2013; The 2013 Portoghese Lectureship), several vignettes of drug discovery campaigns targeting novel allosteric mechanisms will be recounted, along with lessons learned and guidelines that have emerged for successful lead optimization. © 2014 American Chemical Society. Source

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