Inactivation of monoamine oxidase B by analogs of the anticonvulsant agent milacemide [2-(n-pentylamino)acetamide]

Abstract

Analogues of the anticonvulsant agent milacemide (1,2-(n-pentylamino)acetamide), in which the carboxamide group is changed to a nitrile (2), a carbethoxy group (3), a carboxylic acid (4), a cyanomethyl group (5), and a trifluoromethyl group (6), were synthesized and tested as substrates and inactivators of monoamine oxidase B (MAO B). The carboxylic acid was neither a substrate nor an inactivator. The trifluoromethyl compound was not soluble in buffer even when organic cosolvents were added, so it could not be tested. All of the other compounds were both substrates and time-dependent irreversible inactivators of MAO B. A plot of the logarithm of kcat/k(inact) (a measure of the efficiency of the inactivators) versus sigma I (Figure 1) shows a linear free energy relationship between the inactivator efficiency and the electron-withdrawing ability of the substituent. As the electron-withdrawing ability increases, the partition ratio decreases indicating that inactivation is becoming more efficient relative to substrate turnover to product. Milacemide was the least efficient of the compounds tested; the nitrile 2 was the most efficient.

Mechanism of inactivation of monoamine oxidase-B by the anticonvulsant agent milacemide (2-(n-pentylamino)acetamide)

“…We have recently found this to be the case. 23 Experimental Section Analytical Methods. Optical spectra and MAO assays were recorded on either a Perkin-Elmer Lambda 1 or Beckman DU-40 UV/vis spectrophotometer.…”

Rapid Parallel Synthesis of Dipeptide Diphenyl Phosphonate Esters as Inhibitors of Dipeptidyl Peptidases

“…To increase the diversity, a set of Boc-protected N-substituted glycines (5) were prepared by reaction of bromoacetic acid and an amine, followed by Boc-protection of the R-amino function (Scheme 2). 19 Building blocks (4) or ( 5) reacted with hydroxybenzotriazole (HOBt) and a polymer-bound carbodiimide to afford the activated esters (6) (Scheme 3). A limiting amount of building blocks (1) or ( 2) was then added, and after reaction overnight, addition of polymer-bound polyamine captured the excess of activated ester (6) and HOBt.…”

“…The N-terminal building blocks ( 4 ) are commercially available N - tert -butyloxycarbonyl (Boc)-protected amino acids with acid-labile side chain protection. To increase the diversity, a set of Boc-protected N-substituted glycines (5) were prepared by reaction of bromoacetic acid and an amine, followed by Boc-protection of the α -amino function (Scheme ) 2 Synthesis of N -Substituted Glycines a a Reagents: (a) Et 2 O, overnight, rt; (b) Boc 2 O, TEA, dioxane, H 2 O, 5 h, rt. …”

Complexes of selected transition metal ions with n-modified glycine as ligand

“…N-modified glycines have a lot of applications in biomedicine as analogue of anticonvulsant and antiepileptic agent Milacemide or as buildingunits for N-backbone cyclic peptides [8,9].…”