Silverman, Richard, PhD

Information

Name

Silverman, Richard, PhD

Title

John Evans Professor

Email

r-silverman@northwestern.edu

Office Phone

847-491-5653

Office Fax

847-491-7713

Department

Chemistry and Biochemistry Molecular Biology and Cell Biology; Charles Deering McCormick Professor of Teaching Excellence

Office

Silverman Hall 4603 Evanston

Areas of Research

Mechanisms of Drug Action, Molecular Neuroscience

NU Scholar Profile

http://www.scholars.northwestern.edu/expert.asp?u_id=2237

Recent Publications on PubMed

http://www.ncbi.nlm.nih.gov/pubmed?term=Silverman%2C%20Richard%5BFull%20Author%20Name%5D&cmd=DetailsSearch

Current Research

Current Research

The research in my group can be summarized as investigations of the molecular mechanisms of action, rational design, and syntheses of potential medicinal agents, particularly involved in the treatment of several neurodegenerative diseases. We have designed and synthesized several new inactivators of brain aminobutyric acid (GABA) aminotransferase and have investigated their mechanisms. Compounds that inhibit this enzyme exhibit anticonvulsant activity are important in the treatment of addiction. In collaboration with a crystallography group in Basel, we have obtained high-resolution crystal structures of several of our inactivators bound to GABA aminotransferase and are doing structure-based design of new inhibitors.

Another enzyme in which we are interested is nitric oxide synthase, the enzyme that generates the important second messenger nitric oxide. This enzyme exists in three isozymic forms: in brain (nNOS), in macrophage (iNOS, the inducible form), and in endothelial cells (eNOS). Inhibitors of the brain isoform may be important in the treatment of neurotoxicity and stroke, but only if selective inhibition of this isoform can be accomplished to avoid blockage of NO production where it is needed. We have synthesized several new classes of compounds that are highly selective for nNOS, some of which are being tested for neurodegenerative diseases in animals.

L-type Ca2+ channels in mammalian brain neurons have either a CaV1.2 or CaV1.3 pore forming subunit. Prof. D. James Surmeier at our medical school showed that CaV1.3 Ca2+ channels underlie autonomous pacemaking in adult dopaminergic neurons in the substantia nigra pars compacta, and this reliance renders them sensitive to toxins used to create animal models of Parkinson’s disease. Antagonism of these channels with the antihypertensive drug isradipine diminishes their reliance on Ca2+ and the sensitivity of these neurons to toxins, pointing to a potential neuroprotective strategy. However, for neuroprotection without an antihypertensive side effect, compounds that are selective antagonists of the CaV1.3 channel rather than CaV1.2 channel are required. We have synthesized compounds that show high selectivity for CaV1.3 and are modifying their structures for enhanced potency and bioavailability.

Amyotrophic lateral sclerosis (ALS) is a rapid, fatal neurodegenerative disease. Riluzole, the only clinically approved therapeutic for ALS, extends median survival by only 2-3 months. Mutations in the gene encoding copper/zinc superoxide dismutase type 1 (SOD1) are responsible for about 25% of familial ALS cases, whose clinical and pathological features are indistinguishable from those of sporadic ALS, which is the type of ALS responsible for 90% of cases. Mutant SOD1 causes protein aggregation toxicity, which is a hallmark for this familial form of the disease. We have identified several classes of compounds that block protein aggregation as a result of mutant SOD1 and have shown up to 30% life extension in the ALS mouse model. These compounds are being modified for potency and bioavailability enhancement.

Huntington’s disease (HD) is a fatal, autosomal dominant neurodegenerative disorder of mid-life onset, characterized by chorea, cognitive abnormalities, and progressive dementia. Only one disease-modifying therapy, for chorea, is available. Polyglutamine misfolding and aggregation have been implicated as plausible causes of the marked neurodegeneration; however, the therapeutic promise of aggregate inhibition has yet to be realized. We have identified small molecule inhibitors of polyglutamine aggregation. Pharmacokinetic profiling of these compounds has been consistent with excellent drug-like properties. One compound inhibits polyglutamine aggregation in R6/2 mouse brain slices, while reversing the effects of neurodegeneration in a fruit fly model of HD. Further investigation shows that it is non-toxic, has favorable brain pharmacokinetics, reduces huntingtin aggregate size and number in vivo, is neuroprotective as measured by behavioral and neuropathological outcome measures, and significantly extends survival in R6/2 HD mice while reducing striatal neuron loss. These compounds are being modified for enhanced potency and bioavailability.