Application):
The specific aims of the project are to synthesize new chemical compounds and evaluate them for anticonvulsant activity. The long-term objectives include the discovery of new classes of anticonvulsant agents and the development of better anticonvulsant compounds that will lack the adverse effect of currently used antiepileptic agents. Currently, no chemical entity or surgical intervention has offered a complete cure for all types of epilepsy. The research plan is designed to exploit, in a systematic manner, two interesting and hitherto unique lead moieties developed in the investigators laboratories: the cyclic enaminones; and the spiroimidooxy analogs. The experimental design comprises the synthesis of new compounds of each moiety by procedures previously reported in this laboratory, with appropriate modifications. In addition, molecular modeling techniques will be employed, and the Free-Wilson analysis as detailed by P.N. Craig (J. Med. Chem. 1971, 14, 680-684 and J. Med. Chem. 1972, 15, 144-149) will be used in the development of quantitative structure-activity relationships for each moiety. Further, the new moieties and the previous analogs will be analyzed by comparative molecular field analysis-X-ray structure analysis, and in vivo determinations of the pharmacokinetics of transport of various active and inactive derivatives across the blood-brain barrier in rats will be undertaken in collaborating laboratories. An in-depth evaluation of these new classes of anticonvulsants is therefore warranted in order to study the relationship between electronic, steric, and lipophilic effects to anticonvulsant activity and pharmacokinetics so that a predictive mechanism for the feasibility of further synthetic efforts may be justified.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21GM063494-03
Application #
6636686
Study Section
Minority Programs Review Committee (MPRC)
Program Officer
Toliver, Adolphus
Project Start
2001-06-10
Project End
2005-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$188,690
Indirect Cost
Name
Howard University
Department
Type
Schools of Medicine
DUNS #
056282296
City
Washington
State
DC
Country
United States
Zip Code
20059
Jackson, Patrice L; Scott, K R; Southerland, William M et al. (2009) Enaminones 8: CoMFA and CoMSIA studies on some anticonvulsant enaminones. Bioorg Med Chem 17:133-40
Wilson, T L; Jackson, P L; Hanson, C D et al. (2005) QSAR of the anticonvulsant enaminones; molecular modeling aspects and other assessments. Med Chem 1:371-81
Salama, Noha N; Scott, Kenneth R; Eddington, Natalie D (2004) The influence of enaminones on the transport and oral bioavailability of P-glycoprotein substrate therapeutic agents. Int J Pharm 273:135-47
Salama, Noha N; Scott, Kenneth R; Eddington, Natalie D (2004) DM27, an enaminone, modifies the in vitro transport of antiviral therapeutic agents. Biopharm Drug Dispos 25:227-36
Salama, Noha Nabil; Eddington, Natalie D; Payne, Debra et al. (2004) Multidrug resistance and anticonvulsants: new studies with some enaminones. Curr Med Chem 11:2093-113
Eddington, Natalie D; Cox, Donna S; Khurana, Manoj et al. (2003) Synthesis and anticonvulsant activity of enaminones. Part 7. Synthesis and anticonvulsant evaluation of ethyl 4-[(substituted phenyl)amino]-6-methyl-2-oxocyclohex-3-ene-1-carboxylates and their corresponding 5-methylcyclohex-2-enone derivatives. Eur J Med Chem 38:49-64
Khurana, Manoj; Salama, Noha N; Scott, Kenneth R et al. (2003) Preclinical evaluation of the pharmacokinetics, brain uptake and metabolism of E121, an antiepileptic enaminone ester, in rats. Biopharm Drug Dispos 24:397-407