Synthesis of new mannosyl, galactosyl and glucosyl theophylline nucleosides with potential activity as antagonists of adenosine receptors. DEMA-induced cyclization of glycosylideneiminouracils

The synthesis of D-mannosyl, D-galactosyl and D-glucosyl theophylline nucleosides by diethoxymethyl acetate (DEMA)-induced cyclization of 4-amino-5-glycosylideneimino-1,3-dimethyluracil is reported. 8-Methyltheophylline derivatives of the same sugars were also prepared by Ac(2)O/H(+)-induced cyclization of their imine precursors. This approach has allowed beta-D-mannopyranosyl-, alpha-D-galactofuranosyl- and beta-D-glucofuranosyltheophylline nucleosides to be synthesized for the first time. The inhibition of specific binding at A(1), A(2A), A(2B) and A(3) adenosine receptors in the mannose derivatives is also reported.     

Synthesis of di- and tri-substituted adenosine derivatives and their affinities at human adenosine receptor subtypes

The synthesis of 2-(hex-1-ynyl)adenosine derivatives substituted at the N6- and/or 5'-position was carried out on the basis that 2-(hex-1-ynyl)adenosine-5'-N-ethyluronamide (HENECA, 2) showed good affinity and different degree of selectivity for rat adenosine receptors. All new compounds were tested in radioligand binding and adenylyl cyclase assays with recently cloned human A1, A2A, A2B, and A3 adenosine receptors.     

Caffeine and theophylline analogues: correlation of behavioral effects with activity as adenosine receptor antagonists and as phosphodiesterase inhibitors

The behavioral stimulant effects of xanthines, such as caffeine and theophylline, appear to involve blockade of central adenosine receptors. However, 3-isobutyl-1-methylxanthine (IBMX), a potent phosphodiesterase (PDE) inhibitor, produces behavioral depression. The effects of caffeine analogs on open field behavior of mice and potencies as antagonists of adenosine receptors and as inhibitors of three classes of brain PDE have been compared. 1,7-Dimethyl-3-propargylxanthine, 1,3,7-tripropargylxanthine, and 3,7-dimethyl-1-propargylxanthine, which have high affinity for adenosine receptors and weaker activity as PDE inhibitors, all increase behavioral activity. In contrast, 1,3,7-tripropylxanthine, a more potent inhibitor of the brain calcium-independent (Ca-indep) PDEs than 1,3,7-tripropargylxanthine, produces behavioral depression, even though both analogues are potent adenosine receptor antagonists. 7-Benzyl-IBMX, an active receptor antagonist and selective inhibitor of a brain calcium-dependent (Ca-dep) PDE, produces a slight behavioral activation. Xanthines that are potent adenosine receptor antagonists and relatively weak inhibitors of the Ca-indep PDEs reverse the depressant effects of N6-cyclohexyladenosine, while xanthines, such as 1,3,7-tripropylxanthine, that are potent inhibitors of the Ca-indep PDEs, do not. The results suggest that the behavioral effects of xanthines may be determined primarily by relative activity as adenosine receptor antagonists and as inhibitors of brain Ca-indep PDEs.     

Synthesis and biological activity of trisubstituted adenines as A 2A adenosine receptor antagonists

The discovery of new drugs for the treatment of neurodegenerative disorders, such as Parkinson's disease, has become an attractive field of research. Due to the regulation of D(2) receptor activity by A(2A) adenosine receptor, potent and selective ligands of A(2A) subtype could be useful tools to study neurodegenerative disorders. A series of 2,8-disubstituted-9-ethyladenine derivatives was synthesized and tested in binding affinity assay at human adenosine receptors. New compounds showed good affinity and selectivity at A(2A) receptor versus the other subtypes. The introduction of a bromine atom in 8-position increased the affinity of these compounds, leading to ligands with K(i) in the nanomolar range.     

Synthesis of phenylglycine derivatives as potent and selective antagonists of group III metabotropic glutamate receptors

The syntheses of a range of ring and alpha-substituted 4-phosphonophenylglycines are described. A brief discussion of the antagonist activities of compounds 4-10 on group I, II and III metabotropic glutamate (mGlu) receptors expressed in the neonatal rat spinal cord is included.     

Synthesis of benzamide derivatives as TRPV1 antagonists

From hit compounds identified by high throughput screening (HTS), we have found compound 1 as a lead TRPV1 antagonist and confirmed its potential as a treatment for pain. Compound 1 has led to potent TRPV1 antagonistic benzamide derivatives ((+/-)-2: human IC(50)=23 nM, (+/-)-3: human IC(50)=14 nM in the capsaicin-induced calcium influx assay) containing indole and naphthyl moieties, obtained by elaboration of the tryptamine scaffold or via bioisosteric replacements.     

Synthesis of alkyne derivatives of a novel triazolopyrazine as A(2A) adenosine receptor antagonists

A novel [1,2,4]triazolo[1,5-a]pyrazine core was synthesized and coupled with terminal acetylenes. The structure-activity relationship of the alkynes from this novel template was studied for their in vitro and in vivo adenosine A(2A) receptor antagonism. Selected compounds from this series were shown to have potent in vitro and in vivo activities against adenosine A(2A) receptor. Compound 12, in particular, was found to be orally active at 3mg/kg in both a mouse catalepsy model and a 6-hydroxydopamine-lesioned rat model.     

Species differences in structure-activity relationships of adenosine agonists and xanthine antagonists at brain A1 adenosine receptors

A series of 28 adenosine analogs and 17 xanthines has been assessed as inhibitors of binding of N6-R-[3H]phenylisopropyladenosine binding to A1 adenosine receptors in membranes from rat, calf, and guinea pig brain. Potencies of N6-alkyl- and N6-cycloalkyladenosines are similar in the different species. However, the presence of an aryl or heteroaryl moiety in the N6 substituent results in marked species differences with certain such analogs being about 30-fold more potent at receptors in calf than in guinea pig brain. Potencies at receptors in rat brain are intermediate. Conversely, 2-chloroadenosine and 5'-N-ethylcarboxamidoadenosine are about 10-fold less potent at receptors in calf brain than in guinea pig brain. Potencies of xanthines, such as theophylline, caffeine and 1,3-dipropylxanthine are similar in the different species. However, the presence of an 8-phenyl or 8-cycloalkyl substituent results in marked species differences. For example, a xanthine amine conjugate of 1,3-dipropyl-8-phenylxanthine is 9-fold more potent at receptors in calf than in rat brain and 110-fold more potent in calf than in guinea pig brain. Such differences indicate that brain A1 adenosine receptors are not identical in recognition sites for either agonists or antagonists in different mammalian species.     

Synthesis of uracil and theophylline derivatives and study of their effect on glucose transport in rat hepatic cells

A series of uracil and theophyllin derivatives were synthesized. 4-Amino-1,3-dimethyl-5-nonanoylaminouracil displayed the most pronounced effect of the in vitro stimulation of the 2-deoxyglucose transport into hepatic rat cells.     

Triamino derivatives of triazolotriazine and triazolopyrimidine as adenosine A2a receptor antagonists

Piperazine derivatives of 2-furanyl[1,2,4]triazolo[1,5-a][1,3,5]triazine have recently been shown to be potent and selective adenosine A(2a) receptor antagonists. We now demonstrate that potent and selective A(2a) receptor antagonists could still be obtained when the arylpiperazines are separated from the triazolotriazine core structure by an ethylenediamine spacer. Selected analogs bearing this triazolotriazine or the related triazolopyrimidine core structure have been found to be orally active in a mouse catalepsy model of Parkinson's disease.     

3'-deoxyribofuranose derivatives of 1-deaza and 3-deaza-adenosine and their activity as adenosine deaminase inhibitors

2,6-Dichloro-1-deazapurine and 2,6-dichloro-3-deazapurine were coupled with 1,2-O-diacetyl-5-O-benzoyl-3-deoxy-beta-D-ribofuranose. Deprotection of the obtained compounds and reaction with liquid ammonia gave the desired 2-chloroadenine nucleosides, which were dechlorinated to afford the corresponding 1-deaza and 3-deazaadenosine derivatives. Biological studies performed on ADA from calf intestine showed that these new nucleosides are inhibitors of the enzyme.     

Synthesis of hypermodified adenosine derivatives as selective adenosine A3 receptor ligands

We investigated the A(3)AR affinity and selectivity of a series of 2-substituted 3'-azido and 3'-amino adenosine derivatives as well as some 5'-uronamide derivatives thereof. All compounds showed high A(3)AR selectivity. While the 3'-azides appeared to be A(3)AR antagonists with moderate A(3)AR affinity, their 3'-amino congeners exhibit significantly improved A(3)AR affinity and behave as partial agonists. For both the 3'-azides and the 3'-amines, the 5'-methylcarbamoyl modification improved the overall affinity. Introduction of a 2-phenylethynyl substituent provided high affinity for the A(3)AR.     

Synthesis and biological activity of 4-methyl-3,5-dioxane derivatives as thromboxane A2 receptor antagonists

The synthesis and biological activity of novel 4-methyl-3,5-dioxane analogues are described. All compounds were produced through modification of the substituent formally corresponding to the omega-octenol side chain of thromboxane A2 (TXA2), in reference to the structure of SQ29548. Several compounds were found to be potent TXA2 receptor antagonists. Compound 8b was the most effective inhibitor of 9,11-epoxymethano PGH2 (U-46619)-induced human platelet aggregation (IC50 = 7.4 nM).     

Synthesis and biological evaluation of 2-aminothiazoles and their amide derivatives on human adenosine receptors. Lack of effect of 2-aminothiazoles as allosteric enhancers

A number of 2-aminothiazoles (2a-e) and their amide derivatives (4-10) were prepared. The 2-aminothiazoles themselves were tested as allosteric enhancers of agonist binding to human adenosine A(1) receptors. In a variety of experimental set-ups the compounds did not show any such effect, in contrast to earlier findings by another research group. Subsequently the 2-aminothiazoles were used as intermediates in the synthesis of a number of amide derivatives of either aromatic (4-6) or aliphatic nature (7-10). Some of the compounds emerged as moderately active antagonists on human adenosine A(1) and/or A(2A) receptors with lower or negligible potency at adenosine A(3) receptors.     

Synthesis and structure–activity relationships of pyrazolodiazepine derivatives as human P2X7 receptor antagonists

Screening of library compounds has yielded pyrazolodiazepine derivatives with P2X₇ receptor antagonist activity. To explore the structure–activity relationships (SAR) of these pyrazolodiazepines as human P2X₇ receptor antagonists, derivatives were synthesized by substitutions at positions R² and R³ of the pyrazolodiazepine skeleton. Using a 2′(3′)-O-(4-benzoylbenzoyl)ATP (BzATP)-induced fluorescent ethidium uptake assay, the activities of these derivatives were tested in HEK-293 cells stably expressing human P2X₇ receptors. Moreover, the effect of these derivatives was assessed by measuring their effect on IL-1β release induced by BzATP-induced activation of differentiated THP-1 cells. A 2-phenethyl pyrazolodiazepine derivative with a 1-methyl-1H-3-indolyl group at position R² had fivefold greater activity than the derivative with a 5-isoquinolinyl at R². Moreover, a benzyl moiety at R³ had fivefold greater activity than a bicyclic moiety. The stereochemical effect at C-6 showed a preference for the (R)-isomer. Among the series of active derivatives, compound 23b, with a phenethyl group at R¹, a 3-methyl indole at R², and a benzyl at R³, exhibited activity similar to that of the positive control, KN-62, as shown by the inhibitory effects of IL-1β release.     

Quinazolines as adenosine receptor antagonists: SAR and selectivity for A2B receptors

We have recently reported the discovery of numerous new compounds that are selective inhibitors of all of the subtypes of the adenosine receptor family via a pharmacophore database searching and screening strategy. During the course of this work we made the unexpected discovery of a potent A(2B) receptor antagonist, 4-methyl-7-methoxyquinazolyl-2-(2'-amino-4'-imidazolinone) (38, CMB 6446), which showed selectivity for this receptor and functioned as an antagonist, with a binding K(i) value of 112 nM. We explored the effects of both substituent- and ring-structural variations on the receptor affinity in this series of derivatives, which were found to be mostly non-selective adenosine receptor ligands with K(i) values in the micromolar range. Since no enhancement of A(2B) receptor affinity of 38 was achieved, the previously reported pharmacophore-based searching strategy yielded the most potent and selective structurally-related hit in the database originally searched.     

Synthesis of camphecene derivatives using click chemistry methodology and study of their antiviral activity

A series of seventeen tetrazole derivatives of 1,7,7-trimethyl-[2.2.1]bicycloheptane were synthesized using click chemistry methodology and characterized by spectral data. Studies of cytotoxicity and in vitro antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells of the compounds obtained were performed. The structure-activity relationship analysis suggests that to possess virus-inhibiting activity, the compounds of this group should bear oxygen atom with a short linker (C2-C4), either as a hydroxyl group (18, 19, 29), keto-group (21) or as a part of a heterocycle (24). These compounds demonstrated low cytotoxicity along with high anti-viral activity.