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University of Kentucky Doctoral Dissertations Graduate School
2006
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Joshua Roderick Ring
University of Kentucky, [email protected]
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Ring, Joshua Roderick, "SYNTHETIC AROMATIC AGMATINE ANALOGS AS ALLOSTERIC MODULATORS OF
THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR CHANNEL" (2006). University of Kentucky Doctoral
Dissertations. 413.
https://uknowledge.uky.edu/gradschool_diss/413
This Dissertation is brought to you for free and open access by the Graduate School at UKnowledge. It has been
accepted for inclusion in University of Kentucky Doctoral Dissertations by an authorized administrator of
UKnowledge. For more information, please contact [email protected].
ABSTRACT OF DISSERTATION
Joshua Roderick Ring
The Graduate School
University of Kentucky
2006
SYNTHETIC AROMATIC AGMATINE ANALOGS AS ALLOSTERIC
MODULATORS OF THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR
CHANNEL
______________________________________________________
ABSTRACT OF DISSERTATION
______________________________________________________
A dissertation submitted in partial fulfillment of the requirements for the degree of
Doctor of Philosophy in the College of Pharmacy at the University of Kentucky
By
Joshua Roderick Ring
Lexington, Kentucky
Director: Dr. Peter A. Crooks, Professor of Pharmaceutical Sciences
Lexington, Kentucky
2006
Copyright © Joshua Roderick Ring 2006
ABSTRACT OF DISSERTATION
SYNTHETIC AROMATIC AGMATINE ANALOGS AS ALLOSTERIC
MODULATORS OF THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR
CHANNEL
The N-methyl-D-aspartate (NMDA) receptors are highly regulated ligand-gated ion
channels, which are affected by many substrates. Overactivation of the NMDA receptor
can lead to hyperexcitability and a number of neurotoxic effects and neurological
diseases. Agmatine has been demonstrated to act allosterically as an inhibitory modulator
at the polyamine recognition sites of the NMDA receptor complex. The present study
synthesized and evaluated a library of agmatine analogs for their ability to displace
tritiated MK-801 from NMDARs in P2 membrane preparations from rat brains at ligand
concentrations of 1 mM and 50 uM. A full dose-response curve was generated for the
most active compounds, in the presence and absence of a pathological level of spermidine
(100 uM). A forty-five member subset of arylidenamino-guanidino compounds was
synthesized and all were demonstrated to be NMDA receptor inhibitory modulators in the
above assay. Three of these compounds generated biphasic curves, indicating activity at
two binding sites: the postulated high-affinity agmatine binding site, and a low-affinity
site (perhaps the channel itself). (4-Chlorobenzylidenamino)-guanidine hydrochloride
demonstrated an IC50 of 3.6 uM at the former site and 124.5 uM at the latter. Several
computer models were generated to direct further synthesis. Based on the structure-
activity relationship of the arylidenamino-guanidino compounds, a pharmacophore model
of the agmatine binding site of the NMDAR was proposed.
KEYWORDS: Agmatine, N-Methyl-D-Aspartate Receptors, NMDAR Inhibition,
Polyamine Binding Sites, Arylidenamino-Guanidine
Joshua Roderick Ring
_____________________
March 30, 2006
_____________________
SYNTHETIC AROMATIC AGMATINE ANALOGS AS ALLOSTERIC
MODULATORS OF THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR
CHANNEL
By
Joshua Roderick Ring
Peter A. Crooks
_____________________________
Director of Dissertation
Jim R. Pauly
_____________________________
Director of Graduate Studies
March 30, 2006
_____________________________
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Name Date
DISSERTATION
Joshua Roderick Ring
The Graduate School
University of Kentucky
2006
SYNTHETIC AROMATIC AGMATINE ANALOGS AS ALLOSTERIC
MODULATORS OF THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR
CHANNEL
______________________________________________________
DISSERTATION
______________________________________________________
A dissertation submitted in partial fulfillment of the
requirements for the degree of Doctor of Philosophy in the
College of Pharmacy at the University of Kentucky
By
Joshua Roderick Ring
Lexington, Kentucky
Director: Dr. Peter A. Crooks, Professor of Pharmaceutical Sciences
Lexington, Kentucky
2006
Copyright © Joshua Roderick Ring 2006
Acknowledgments
I would like to use this opportunity to express my appreciation for a myriad of
kind and generous souls who have joined me in this journey. Firstly, Dr. Peter Crooks,
who has guided me throughout the course of this work with patience and passion, and Dr.
John Littleton, who led me through the perils of pharmacology. Secondly, those who
have been members of my dissertation committee who have taken the time to challenge
me: Dr. Marcos Oliveira, Dr. Jim Geddes, Dr. Jurgen Rohr, and Dr. George Digenis. I
would also like to thank Dr. Bettye Hollins for serving as my outside examiner for the
defense of this dissertation.
The continuous help and support of many people has allowed me to learn and
grow as a scientist in the laboratory. The entire group of Dr. Crooks has been
instrumental in my chemical knowledge and discovery, especially Dr. Sundar
Neelakantan and my cohort Aaron Haubner. I must also express my gratitude to the
group of Dr. Littleton for patiently allowing me to learn some laboratory pharmacology,
particularly Robert Holley and Dr. D. Trent Rogers. Dr. Sean Parkin was generous
enough to generate the X-Ray crystallographical material contained in this work, and Dr.
Fang Zheng spent many hours assisting me in the creation of the PLS and ANN models.
To my parents, my sisters, and my friends: thank you all for being there when I
needed you. And to Leigh, for listening and always loving.
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Description:Ring, Joshua Roderick, "SYNTHETIC AROMATIC AGMATINE ANALOGS AS NMDAR complexes with a relatively larger amount of NR2B subunits
