Research Overview

The research in the Schiefer lab is focused on CNS drug discovery. We are a genuine multi-disciplinary research group. Specific activities carried out in the Schiefer lab include: organic synthesis; bioanalytical characterization of efficacy (in collaboration); in vitro metabolic stability and reactivity analysis; in vivo analysis of brain:plasma ratio and pharmacokinetics (using HPLC and LC-MS-MS); analysis of pharmacodynamic markers of efficacy (via ELISA, western blot, or microscopy); and in vivo behavioral efficacy studies using murine models of learning, memory, and motor function. Our projects can be broadly classified into two categories: 1) target identification; and 2) hit-to-lead optimization. Target identification projects focus on using techniques in chemical biology to understand the molecular targets and mechanism of action of small molecules with interesting CNS activity. Ideally the knowledge gained during target ID studies will be used to produce novel proprietary small molecules, followed by hit-to-lead optimization.

 

 

 

 

 

Attenuated Nitric Oxide (NO) Mimetic Furoxans as Novel Neurorestorative Agents

 

 

 

 

 

 

 

 

 

 

NO mimetics activate an intracellular 2nd messenger known as soluble guanylyl cyclase (sGC) leading to increased cyclic GMP (cGMP) production and increased phosphorylation/activation of CREB (pCREB). Modulation of pCREB and downstream up-regulation of BDNF is a validated pathway for therapeutic intervention to treat a variety of neurodegenerative scenarios; including, ischemic stroke, traumatic brain injury (TBI), and Alzheimer’s disease (AD).

 

Furoxans are distinct because they exhibit “tunable” NO mimetic effects. Dr. Schiefer pioneered the discovery of furoxans as novel neuroprotective and procognitive agents during his graduate at the University of Illinois at Chicago (UIC). The Schiefer lab is in the process of developing furoxans as novel therapies for AD.

 

See Horton, A.; et. al.;  Journal of Medicinal Chemistry, 2018; 61(10), 4593-4607.

 

Financial Support:

National Institute on Aging (NIA)

R01AG057598 (Schiefer [PI])

[Total: $1,925,3070]; 2018-2023

Alzheimer's Association

2015 New Investigator Research Grant (Schiefer [PI])

[Total: $100,000]; 2015-2017

 

American Association of Colleges of Pharmacy

2014 New Investigator Award (Schiefer [PI])

[Total: $10,000]; 2014

 

University of Toledo Office of Undergraduate Research

In total, eight students have been awarded summer salary support to work on this project. [Total: $25,500]


Novel approaches for studying the drug targets and lethality of synthetic cathinones (i.e., bath salts).

We have begun pilot studies on synthetic cathinones using zebrafish models in collaboration with the labs of Dr. F. Scott Hall and Dr. Fred Williams in the Department of Pharmacology and Experimental Therapeutics at the University of Toledo. This includes the synthesis of scheduled substances for lethality studies and the synthesis of relevant novel chemical probes for in vivo target identification and associated chemical biology techniques.

Financial Support:

National Institute on Drug Abuse (NIDA)

R03DA045833 (Schiefer [PI])

[Total: $150,000]; 2018-2020

National Institute on Drug Abuse (NIDA)

R03DA045350 (Hall[PI])

[Total: $150,000]; 2018-2020

Specific Projects

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