Lucia Cecchi

Synthesis of some tricyclic heteroaromatic systems and their A1 and A2a adenosine binding activity

Summary The syntheses, A1 and A2a adenosine receptor affinities and structure-activity relationships of some 2-aryl-1,2,4-tri-azolo [1,5-a]quinoxalines, 2-arylimidazo[1,2-a]quinoxalines, 1-arylimidazo[1,5-a]quinoxalines are reported and compared with that of a previously reported 2-phenylpyrazolo[ 1,5-a]quinoxaline. The results show that some triazoloquinoxalines are potent and specific A, adenosine receptor ligands and that the replacement of either nitrogen at position 1 or 3 of the triazoloquinoxaline moiety with a CH brought about a decrease in affinity at both adenosine receptors.

Synthesis and A1 and A2A adenosine binding activity of some pyrano [2,3-c] pyrazol-4-ones

A series of pyrano[2,3-c]pyrazol-4-ones was synthesized and evaluated for bovine brain adenosine A1 and A2A receptor binding affinity. Substituents at positions 5 and/or 6 were varied in order to define the structure-activity relationships in these new kinds of adenosine receptor ligands. The most selective and potent ligand among the reported compounds was the 1,4-dihydro-1-phenyl-3-methyl-6-(3-aminophenyl)-pyrano[2,3-c]pyraz ol-4-one 11 which showed a 27-fold selectivity for A1 receptor and a Ki value of 84 nM.

Pyrazolo[4,5-c]quinolines. 2. Synthesis and specific inhibition of benzodiazepine receptor binding.

A series of 1-aryl-3,5-dimethyl-4,5-dihydro-1H-pyrazolo[4,5-c]quinolin-4-ones (2a-e) and 1-aryl-3-methyl-1H-pyrazolo[4,5-c]quinolines (3-7a-e) bearing different substituents at position 4 were prepared and tested for their ability to displace specific [3H]flunitrazepam binding from bovine brain membranes. The 5-N-methyl derivatives 2a-c,e were the compounds that bound with the highest affinity within this class. The replacement of the carbonyl group with other substituents and the resulting aromatization of the pyridine moiety greatly decreased the binding affinity. From a Lineweaver-Burk analysis on the most active compound 2b, it appears that the inhibition is a competitive one.

The correct synthesis of 2,3-dihydro-2-aryl-4-r-[1]benzopyrano[4,3-c]pyrazole-3-ones.

Abstract The correct synthesis of the title compounds 1a–b and 2a–b is described. The claimed synthesis of 2a from 2-methyl-3-chromonecarbonitrile is shown not to lead to 2a , as previously reported but to 1,4-dihydro-1-phenyl-3-methyl[1]benzopyrano[3,4-d]pyrazole-4-one 10a.

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.

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 and structure-activity relationships of 1-aminophthalazinium salts as GABAA receptor antagonists

Abstract The synthesis and in vitro GABA A activity as GABA A antagonists of some 1-aminophthalazinium salts and imidazophthalazines are reported. Structure—activity relationships and a molecular modelling study allowed us to define the features which determine receptor affinity within this class of compounds.

Tricyclic heteroaromatic systems. synthesis and benzodiazepine receptor affinity of 2-substituted- 1-benzopyrano [3,4-d] oxazol-4-ones, -thiazol-4-ones, and -imidazol-4-ones

Abstract A number of 2-aryl-substituted-l-benzopyrano[3,4-d] oxazol-4-ones 1, -thiazol-4-ones 2 and -imidazol-4-ones 3 were synthesized. Benzodiazepine receptor (BZR) binding assays were performed on these series of tricyclic heteroaromatic systems. None of the tested compounds showed detectable affinity for BZR. Comparative structure-activity relationship analysis between the reported compounds and some known BZR ligands of similar size and shape revealed that, according to a two-dimensional schematic representation of the interaction of these kinds of tricyclic heteroaromatic systems with the BZR recognition site, the nature of the optional a, proton acceptor is of significant importance in the receptor-ligand interaction.

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.

SYNTHESIS OF NEW 6,7‐DISUBSTITUTED 2‐PHENYLPYRAZOLO(1,5‐A)PYRIMIDINES

Das Phen -amino-pyrazol (I) reagiert mit Ethoxymethylendicarbonyl-Verbindungen (II), (V) bzw. (VIII) zu den Pyrazolo-pyrimidinen (III), (VI), (IX) und (X), welche mit Natriumborhydrid reduziert bzw. hydriert werden konnen.