title: Structure-activity analysis of guanidine group in agmatine for brain agmatinase.
abstract: To identify a selective inhibitor of mammalian agmatinase, screening was performed on four analogues of agmatine with modifications directly to the guanidine group, six analogues with modifications to the carbon-amine chain, and one analogue with modifications at both ends of the molecule. Control compounds were aminoguanidine and 7-nitroindazole, known inhibitors of the three isoforms (i, e, n) of nitric oxide synthase (NOS), and arcaine, a known inhibitor of the glutamate NMDA receptor. These compounds were compared for inhibition of rat agmatinase and arginine decarboxylase (ADC) activities. Results were studied by ab initio Hartee-Fock descriptors based on optimized geometries and van der Waals radii. Linear correlations were obtained using various geometric and electronic descriptors of the carbon (C), nitrogen (N), and hydrogen (H) atoms in the guanidine moiety. The best fit equation for percent activity remaining of rat agmatinase was = 0.3225 D + 72.76 D1916 + 64.97 D1920 - 192.58 H21 - 253.09 (r = 0.89), where D is the calculated dipole moment, D1916 and D1920 are the N19-N16 and N19-N20 distances, respectively, and H21 is the charge on H21. This agmatinase equation is distinct from the equations fit for ADC, the three NOS isoforms, and inhibition of NMDA receptor binding.
authors.affiliation: Department of Chemistry, Jackson State University, Jackson, Mississippi 39217, USA. mhuang@chem.jsums.edu
authors.forename: M-J
authors.initials: MJ
authors.lastname: Huang
authors.forename: S
authors.initials: S
authors.lastname: Regunathan
authors.forename: M
authors.initials: M
authors.lastname: Botta
authors.forename: K
authors.initials: K
authors.lastname: Lee
authors.forename: E
authors.initials: E
authors.lastname: McClendon
authors.forename: G B
authors.initials: GB
authors.lastname: Yi
authors.forename: M L
authors.initials: ML
authors.lastname: Pedersen
authors.forename: D B
authors.initials: DB
authors.lastname: Berkowitz
authors.forename: G
authors.initials: G
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Travagli
authors.forename: J E
authors.initials: JE
authors.lastname: Piletz
mesh_terms: D000376:Agmatine / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D006146:Guanidines / Q000737:chemistry*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012044:Regression Analysis; D014512:Ureohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D006146:Guanidines; D007527:Isoenzymes; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D000376:Agmatine; D019001:Nitric Oxide Synthase; D014512:Ureohydrolases; C019625:agmatinase; D002262:Carboxy-Lyases; C019722:arginine decarboxylase