Epilepsy is a debilitating neurological disorder that affects approximately 50-60 million people worldwide. Unfortunately, only 70% of patients are effectively treated with available anticonvulsant drugs. The goal of this R21 grant application is to characterize unique galantine-based compounds discovered in our laboratory for their ability to treat pharmaco-resistant epilepsy. Galantine is an anticonvulsant neuropeptide that provides a unique opportunity to develop novel antiepileptic drugs, but this peptide exhibits poor metabolic stability and does not penetrate the blood-brain-barrier. Our results suggest that we have successfully designed systemically-active anticonvulsant galantine analogs that are: metabolically and conformationally more stable, AND can penetrate the blood- brain-barrier, AND retain high affinity toward two galantine receptor subtypes. The gain of the systemic bioavailability of the galantine analogs was a result of a judicious combination of several chemical modifications, of which a specific lip amino acid coupled to cationization appeared to be critical components. In the present grant application, we propose to test a hypothesis that by optimizing the length of the critical lip amino acid substituent, we will improve systemic activity of the galanin analogs, without affecting receptor binding properties. Correlations between the length of the lipoamino acid and several physico-chemical and functional parameters will be used to dissect a role of metabolic stability, lipophilicity and conformation in improving systemic bioavailability of the galanin analogs, thus providing an important mechanistic insight into how the lipoamino acid may increase systemic activity of these unique anticonvulsant peptides.

Public Health Relevance

This project aims to advance a greater understanding of the role of galanin and their receptors in epilepsy. We propose to synthesize a series of unique antiepileptic compounds that can access critical parts of the brain responsible for the initiation and propagation of seizure activity. Such compounds will be used to study the mechanisms of seizures in epilepsy and ultimately to a novel therapeutic strategy for preventing, slowing or halting the development of epilepsy. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS059669-01A2
Application #
7531411
Study Section
Special Emphasis Panel (ZRG1-BDCN-A (11))
Program Officer
Stewart, Randall R
Project Start
2008-08-01
Project End
2010-02-28
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
1
Fiscal Year
2008
Total Cost
$197,531
Indirect Cost
Name
University of Utah
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Metcalf, Cameron S; Klein, Brian D; McDougle, Daniel R et al. (2015) Analgesic properties of a peripherally acting and GalR2 receptor-preferring galanin analog in inflammatory, neuropathic, and acute pain models. J Pharmacol Exp Ther 352:185-93
Flynn, Sean P; White, H Steve (2015) Regulation of glucose and insulin release following acute and repeated treatment with the synthetic galanin analog NAX-5055. Neuropeptides 50:35-42
Jequier Gygax, Marine; Klein, Brian D; White, H Steve et al. (2014) Efficacy and tolerability of the galanin analog NAX 5055 in the multiple-hit rat model of symptomatic infantile spasms. Epilepsy Res 108:98-108
Robertson, Charles R; Pruess, Timothy H; Grussendorf, Erin et al. (2012) Generating orally active galanin analogues with analgesic activities. ChemMedChem 7:903-9
Green, Brad R; Smith, Misty; White, Karen L et al. (2011) Analgesic neuropeptide W suppresses seizures in the brain revealed by rational repositioning and peptide engineering. ACS Chem Neurosci 2:51-6
Green, Brad R; White, Karen L; McDougle, Daniel R et al. (2010) Introduction of lipidization-cationization motifs affords systemically bioavailable neuropeptide Y and neurotensin analogs with anticonvulsant activities. J Pept Sci 16:486-95
Robertson, Charles R; Scholl, Erika Adkins; Pruess, Timothy H et al. (2010) Engineering galanin analogues that discriminate between GalR1 and GalR2 receptor subtypes and exhibit anticonvulsant activity following systemic delivery. J Med Chem 53:1871-5
Lee, Hee-Kyoung; Smith, Misty D; Smith, Brian J et al. (2009) Anticonvulsant Met-enkephalin analogues containing backbone spacers reveal alternative non-opioid signaling in the brain. ACS Chem Biol 4:659-71
White, H Steve; Scholl, Erika A; Klein, Brian D et al. (2009) Developing novel antiepileptic drugs: characterization of NAX 5055, a systemically-active galanin analog, in epilepsy models. Neurotherapeutics 6:372-80
Zhang, Liuyin; Robertson, Charles R; Green, Brad R et al. (2009) Structural requirements for a lipoamino acid in modulating the anticonvulsant activities of systemically active galanin analogues. J Med Chem 52:1310-6

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