Mataija D

References (5)

Title : Differential binding of phenothiazine urea derivatives to wild-type human cholinesterases and butyrylcholinesterase mutants - Darvesh_2010_Bioorg.Med.Chem_18_2232
Author(s) : Darvesh S , Pottie IR , Darvesh KV , McDonald RS , Walsh R , Conrad S , Penwell A , Mataija D , Martin E
Ref : Bioorganic & Medicinal Chemistry , 18 :2232 , 2010
Abstract : A series of N-10 urea derivatives of phenothiazine was synthesized and each compound was evaluated for its ability to inhibit human cholinesterases. Most were specific inhibitors of BuChE. However, the potent inhibitory effects on both cholinesterases of one sub-class, the cationic aminoureas, provide an additional binding mechanism to cholinesterases for these compounds. The comparative effects of aminoureas on wild-type BuChE and several BuChE mutants indicate a binding process involving salt linkage with the aspartate of the cholinesterase peripheral anionic site. The effect of such compounds on cholinesterase activity at high substrate concentration supports ionic interaction of aminoureas at the peripheral anionic site.
ESTHER : Darvesh_2010_Bioorg.Med.Chem_18_2232
PubMedSearch : Darvesh_2010_Bioorg.Med.Chem_18_2232
PubMedID: 20181484

Title : Carbamates with differential mechanism of inhibition toward acetylcholinesterase and butyrylcholinesterase - Darvesh_2008_J.Med.Chem_51_4200
Author(s) : Darvesh S , Darvesh KV , McDonald RS , Mataija D , Walsh R , Mothana S , Lockridge O , Martin E
Ref : Journal of Medicinal Chemistry , 51 :4200 , 2008
Abstract : Most carbamates are pseudoirreversible inhibitors of cholinesterases. Phenothiazine carbamates exhibit this inhibition of acetylcholinesterase but produce reversible inhibition of butyrylcholinesterase, suggesting that they do not form a covalent bond with the catalytic serine. This atypical inhibition is attributable to pi-pi interaction of the phenothiazine moiety with F329 and Y332 in butyrylcholinesterase. These residues are in a helical segment, referred to here as the E-helix because it contains E325 of the catalytic triad. The involvement of the E-helix in phenothiazine carbamate reversible inhibition of butyrylcholinesterase is confirmed using mutants of this enzyme at A328, F329, or Y332 that show typical pseudoirreversible inhibition. Thus, in addition to various domains of the butyrylcholinesterase active site gorge, such as the peripheral anionic site and the pi-cationic site of the Omega-loop, the E-helix represents a domain that could be exploited for development of specific inhibitors to treat dementias.
ESTHER : Darvesh_2008_J.Med.Chem_51_4200
PubMedSearch : Darvesh_2008_J.Med.Chem_51_4200
PubMedID: 18570368

Title : Selective reversible inhibition of human butyrylcholinesterase by aryl amide derivatives of phenothiazine - Darvesh_2007_Bioorg.Med.Chem_15_6367
Author(s) : Darvesh S , McDonald RS , Darvesh KV , Mataija D , Conrad S , Gomez G , Walsh R , Martin E
Ref : Bioorganic & Medicinal Chemistry , 15 :6367 , 2007
Abstract : Evidence suggests that specific inhibition of butyrylcholinesterase may be an appropriate focus for the development of more effective drugs to treat dementias such as Alzheimer's disease. Butyrylcholinesterase is a co-regulator of cholinergic neurotransmission and its activity is increased in Alzheimer's disease, and is associated with all neuropathological lesions in this disease. Some selective butyrylcholinesterase inhibitors have already been reported to increase acetylcholine levels and to reduce the formation of abnormal amyloid found in Alzheimer's disease. Synthesized N-(10)-aryl and N-(10)-alkylaryl amides of phenothiazine are specific inhibitors of butyrylcholinesterase. In some cases, inhibition constants in the nanomolar range are achieved. Enzyme specificity and inhibitor potency of these molecules can be related to molecular volumes, steric and electronic factors. Computed logP values indicate high potential for these compounds to cross the blood-brain barrier. Use of such butyrylcholinesterase inhibitors could provide direct evidence for the importance of this enzyme in the normal nervous system and in Alzheimer's disease.
ESTHER : Darvesh_2007_Bioorg.Med.Chem_15_6367
PubMedSearch : Darvesh_2007_Bioorg.Med.Chem_15_6367
PubMedID: 17681768

Title : On the active site for hydrolysis of aryl amides and choline esters by human cholinesterases - Darvesh_2006_Bioorg.Med.Chem_14_4586
Author(s) : Darvesh S , McDonald RS , Darvesh KV , Mataija D , Mothana S , Cook H , Carneiro KM , Richard N , Walsh R , Martin E
Ref : Bioorganic & Medicinal Chemistry , 14 :4586 , 2006
Abstract : Cholinesterases, in addition to their well-known esterase action, also show an aryl acylamidase (AAA) activity whereby they catalyze the hydrolysis of amides of certain aromatic amines. The biological function of this catalysis is not known. Furthermore, it is not known whether the esterase catalytic site is involved in the AAA activity of cholinesterases. It has been speculated that the AAA activity, especially that of butyrylcholinesterase (BuChE), may be important in the development of the nervous system and in pathological processes such as formation of neuritic plaques in Alzheimer's disease (AD). The substrate generally used to study the AAA activity of cholinesterases is N-(2-nitrophenyl)acetamide. However, use of this substrate requires high concentrations of enzyme and substrate, and prolonged periods of incubation at elevated temperature. As a consequence, difficulties in performing kinetic analysis of AAA activity associated with cholinesterases have hampered understanding this activity. Because of its potential biological importance, we sought to develop a more efficient and specific substrate for use in studying the AAA activity associated with BuChE, and for exploring the catalytic site for this hydrolysis. Here, we describe the structure-activity relationships for hydrolysis of anilides by cholinesterases. These studies led to a substrate, N-(2-nitrophenyl)trifluoroacetamide, that was hydrolyzed several orders of magnitude faster than N-(2-nitrophenyl)acetamide by cholinesterases. Also, larger N-(2-nitrophenyl)alkylamides were found to be more rapidly hydrolyzed by BuChE than N-(2-nitrophenyl)acetamide and, in addition, were more specific for hydrolysis by BuChE. Thus, N-(2-nitrophenyl)alkylamides with six to eight carbon atoms in the acyl group represent suitable specific substrates to investigate further the function of the AAA activity of BuChE. Based on the substrate structure-activity relationships and kinetic studies, the hydrolysis of anilides and esters of choline appears to utilize the same catalytic site in BuChE.
ESTHER : Darvesh_2006_Bioorg.Med.Chem_14_4586
PubMedSearch : Darvesh_2006_Bioorg.Med.Chem_14_4586
PubMedID: 16504521

Title : Structure-activity relationships for inhibition of human cholinesterases by alkyl amide phenothiazine derivatives - Darvesh_2005_Bioorg.Med.Chem_13_211
Author(s) : Darvesh S , McDonald RS , Penwell A , Conrad S , Darvesh KV , Mataija D , Gomez G , Caines A , Walsh R , Martin E
Ref : Bioorganic & Medicinal Chemistry , 13 :211 , 2005
Abstract : Several lines of evidence indicate that inhibition of butyrylcholinesterase (BuChE) is important in the treatment of certain dementias. Further testing of this concept requires inhibitors that are both BuChE-selective and robust. N-alkyl derivatives (2, 3, 4) of phenothiazine (1) have previously been found to inhibit only BuChE in a mechanism involving pi-pi interaction between the phenothiazine tricyclic ring system and aromatic residues in the active site gorge. To explore features of phenothiazines that affect the selectivity and potency of BuChE inhibition, a series of N-carbonyl derivatives (5-25) was synthesized and examined for the ability to inhibit cholinesterases. Some of the synthesized derivatives also inhibited AChE through a different mechanism involving carbonyl interaction within the active site gorge. Binding of these derivatives takes place within the gorge, since this inhibition disappears when the molecular volume of the derivative exceeds the estimated active site gorge volume of this enzyme. In contrast, BuChE, with a much larger active site gorge, exhibited inhibition that increased directly with the molecular volumes of the derivatives. This study describes two distinct mechanisms for binding phenothiazine amide derivatives to BuChE and AChE. Molecular volume was found to be an important parameter for BuChE-specific inhibition.
ESTHER : Darvesh_2005_Bioorg.Med.Chem_13_211
PubMedSearch : Darvesh_2005_Bioorg.Med.Chem_13_211
PubMedID: 15582466