Chiara Costagli

Inhibition of cholinesterase-associated aryl acylamidase activity by anticholinesterase agents : Focus on drugs potentially effective in Alzheimer's disease

The potency of a series of anticholinesterase (anti-ChE) agents and serotonin-related amines as inhibitors of the aryl acylamidase (AAA) activity associated with electric eel acetylcholinesterase (AChE) (EC 3.1.1.7) and horse serum butyrylcholinesterase (BuChE) (EC 3.1.1.8) was examined and compared with the potency of the same compounds as ChE inhibitors. Neostigmine, physostigmine, BW 284C51, (+/-)-huperzine A, E2020, tacrine, edrophonium and heptyl-physostigmine were, in that order, the most potent in inhibiting eel AChE-associated AAA activity, their inhibitor constant (Ki) values being in the range 0.02-0.37 microM. The rank order of the same compounds as AChE inhibitors basically paralleled that of AAA, although they were in general stronger on AChE (Ki = 0.001-0.05). The peripheral anionic site inhibitors propidium and gallamine were inactive on AChE-associated AAA. Serotonin and its derivatives were slightly stronger on AAA (Ki = 7.5-30 microM) than on AChE (Ki = 20-140 microM). Tacrine (IC50 = 0.03 microM), diisopropylfluorophosphate (IC50 = 0.04 microM), heptyl-physostigmine (IC50 = 0.11 microM), physostigmine (IC50 = 0.15 microM) and tetra-iso-propylpyrophosphoramide (iso-OMPA) (IC50 = 0.75 microM) were the most potent in inhibiting horse serum BuChE-associated AAA activity. Serotonin and related amines were very weak on BuChE-associated AAA activity. These results indicate that the inhibitory potencies of the active site anti-ChE agents on the AAA activity associated with eel AChE and horse serum BuChE are closely correlated with their action on the respective ChE. In addition, the efficacy of tacrine, E2020, heptyl-physostigmine and (+/-)-huperzine A in the treatment of Alzheimers disease is unlikely to be related to the action of these drugs on ChE-associated AAA.

Synthesis of a set of ethyl 1-carbamoyl-3-oxoquinoxaline-2-carboxylates and of their constrained analogue imidazo[1,5-a]quinoxaline-1,3,4-triones as glycine/NMDA receptor antagonists

The synthesis and glycine/NMDA and AMPA receptor affinities of a set of ethyl (+/-) 1-N-carbamoyl-1,2,3,4-tetrahydro-3-oxoquinoxaline-2-carboxylates 1-11 and those of their constrained analogue (+/-) 1,2,3,3a,4,5-hexahydroimidazo[1,5-a]quinoxaline-1,3,4-triones 12-24 are reported. Compounds 1-11 bear a side-chain at position 1 which has been spatially constrained in compounds 12-24. Most of the reported tricyclic derivatives 12-24 showed glycine/NMDA binding activity comparable to that of their corresponding bicyclic analogues 1-11 providing further evidence that the spatial orientation of the side-chain is an important structural requirement for glycine/NMDA receptor antagonists.

Characterization of the mechanism of anticonvulsant activity for a selected set of putative AMPA receptor antagonists

A selected set of 1-aryl-7,8-methylenedioxy-2,3-benzodiazepin-4-ones and their analogues were evaluated for their ability to bind the competitive and noncompetitive sites of the AMPA receptors complex as well as to the glycine site of the NMDA receptors. The results put in evidence that most of the test compounds, despite a close structural similarity with GYKI 52466, possess a significantly different pharmacological profile.

3-Hydroxy-1H-quinazoline-2,4-dione derivatives as new antagonists at ionotropic glutamate receptors: molecular modeling and pharmacological studies.

Based on our 3-hydroxy-7-chloroquinazoline-2,4-dione derivatives, previously reported as antagonists at ionotropic glutamate receptors, we synthesized new 3-hydroxyquinazoline-2,4-diones bearing a trifluoromethyl group at the 7-position and different groups at position 6. Glycine/NMDA, AMPA and kainate receptor binding data showed that the 7-trifluoromethyl residue increased AMPA and kainate receptor affinity and selectivity, with respect to the 7-chlorine atom. Among the probed 6-substituents, the 6-(1,2,4-triazol-4-yl) group (compound 8) was the most advantageous for AMPA receptor affinity and selectivity. Derivative 8 demonstrated to be effective in decreasing neuronal damage produced by oxygen and glucose deprivation in organotypic rat hippocampal slices and also showed anticonvulsant effects in pentylenetetrazole-induced convulsions. The previously reported kainate receptor antagonist 6-(2-carboxybenzoyl)-amino-7-chloro-3-hydroxyquinazoline-2,4-dione 3 prevented the failure of neurotransmission induced by oxygen and glucose deprivation in the CA1 region of rat hippocampal slices.

Tandem 3D-QSARs approach as a valuable tool to predict binding affinity data: design of new Gly/NMDA receptor antagonists as a key study.

Quantitative structure-activity relationships (QSARs) represent a very well consolidated computational approach to correlate structural or property descriptors of chemical compounds with their chemical or biological activities. We have recently reported that autocorrelation Molecular Electrostatic Potential (autoMEP) vectors in combination to Partial Least-Square (PLS) analysis or to Response Surface Analysis (RSA) can represent an interesting alternative 3D-QSAR strategy. In the present paper, we would like to present how the applicability of in tandem linear and nonlinear 3D-QSAR methods (autoMEP/PLS&RSA) can help to predict binding affinity data of a new set of N-methyl-d-aspartate (Gly/NMDA) receptor antagonists.

Reversible Inhibition of Cholinesterases by Opioids: Possible Pharmacological Consequences

The inhibitory potency of opioids belonging to different structural categories on electric eel and rat brain acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE) was investigated.

Synthesis of 2-substituted-6,8-dichloro-3,4-dihydro-3-oxo-2H-1,4-benzothiazine-1,1-dioxides and -1-oxides as glycine-NMDA receptor antagonists

A number of 2-substituted-3,4-dihydro-3-oxo-6,8-dichloro-2H-1, 4-benzothiazine-1,1-dioxides (1-2a-b) and -1-oxides (3-4a-b) bioisosters of RPR 104632 in which the 3-carboxylic group was replaced by a carbonyl group were synthesized. Comparative in vitro pharmacological studies on this series of RPR 104632 analogs were performed using receptor binding assays. None of these compounds showed detectable binding affinity for the glycine-NMDA receptor.

Synthesis, benzodiazepine receptor affinity and in vivo testing of 3-aryl-4,7-dihydro-6-(N1′-alkylpyrazol-3′ - or 5′-yl)pyrazolo[1,5-a]pyrimidin-7-ones

Summary The synthesis of a series of 3-aryl-4,7-dihydro-6-( N 1 ′-alkylpyrazol-3′- or 5′-yl)pyrazolo[1,5- a ]pyrimidin-7-ones and their in vitro biological evaluation as ligands for benzodiazepine receptor (BzR) are described. The in vitro activities, as determined by an analysis of GABA (γ-aminobutyric acid) shift ratios, and binding affinities of these compounds to BzR are compared in terms of the electronic, lipophilic and steric effect changes of their substituents either at the 3-position or at the N 1 ′ of 6-(pyrazol-3′(5′)-yl) moiety. The most interesting compounds were tested in vivo.

Synthesis, glycine/NMDA and AMPA binding activity of some new 2,5,6-trioxopyrazino[1,2,3-de]quinoxalines and of their restricted analogs 2,5-dioxo- and 4,5-dioxoimidazo[1,5,4-de]quinoxalines.

The synthesis of some new 1,2,3,5,6,7‐hexahydro‐2,5,6‐tri‐oxopyrazino[ 1,2,3‐de]quinoxalines 1c—g and of their restricted analogs 2,4,5,6‐tetrahydro‐2,5‐dioxo‐1H‐ 2a—g and 5,6‐dihydro‐4, 5‐dioxo‐4H‐imidazo[1,5,4‐de]quinoxalines 3a—d is reported. Compounds 1c—g, 2a—g, and 3a—d were tested for their binding activity at the glycine/NMDA and AMPA receptors. The results show that only the 6,6,6‐tricyclic derivatives 1c—g are able to bind to the glycine/NMDA and AMPA receptors, although with lower affinity than the previously reported lead compounds 1a—b. In contrast, the 5,6,6‐tricyclic derivatives 2a—g are inactive at both receptors and only one 4,5‐dioxoimidazoquinoxaline (3b) displays a weak glycine/NMDA receptor affinity.