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1.
Pharmaceuticals (Basel) ; 15(12)2022 Dec 14.
Article in English | MEDLINE | ID: mdl-36559010

ABSTRACT

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by decreased synaptic transmission and cerebral atrophy with appearance of amyloid plaques and neurofibrillary tangles. Cognitive, functional, and behavioral alterations are commonly associated with the disease. Different pathophysiological pathways of AD have been proposed, some of which interact and influence one another. Current treatment for AD mainly involves the use of therapeutic agents to alleviate the symptoms in AD patients. The conventional single-target treatment approaches do not often cause the desired effect in the disease due to its multifactorial origin. Thus, multi-target strategies have since been undertaken, which aim to simultaneously target multiple targets involved in the development of AD. In this review, we provide an overview of the pathogenesis of AD and the current drug therapies for the disease. Additionally, rationales of the multi-target approaches and examples of multi-target drugs with pharmacological actions against AD are also discussed.

2.
Front Cell Infect Microbiol ; 12: 987683, 2022.
Article in English | MEDLINE | ID: mdl-36250046

ABSTRACT

Porphyromonas gingivalis is a major pathogenic bacterium involved in the pathogenesis of periodontitis. Citrullination has been reported as the underlying mechanism of the pathogenesis, which relies on the interplay between two virulence factors of the bacterium, namely gingipain R and the bacterial peptidyl arginine deiminase. Gingipain R cleaves host proteins to expose the C-terminal arginines for peptidyl arginine deiminase to citrullinate and generate citrullinated proteins. Apart from carrying out citrullination in the periodontium, the bacterium is found capable of citrullinating proteins present in the host synovial tissues, atherosclerotic plaques and neurons. Studies have suggested that both virulence factors are the key factors that trigger distal effects mediated by citrullination, leading to the development of some non-communicable diseases, such as rheumatoid arthritis, atherosclerosis, and Alzheimer's disease. Thus, inhibition of these virulence factors not only can mitigate periodontitis, but also can provide new therapeutic solutions for systematic diseases involving bacterial citrullination. Herein, we described both these proteins in terms of their unique structural conformations and biological relevance to different human diseases. Moreover, investigations of inhibitory actions on the enzymes are also enumerated. New approaches for identifying inhibitors for peptidyl arginine deiminase through drug repurposing and virtual screening are also discussed.


Subject(s)
Periodontitis , Porphyromonas gingivalis , Gingipain Cysteine Endopeptidases , Humans , Hydrolases , Periodontitis/microbiology , Protein-Arginine Deiminases/metabolism , Virulence Factors
3.
Saudi J Biol Sci ; 29(4): 2573-2581, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35531186

ABSTRACT

Porphyromonas gingivalis, the cause of periodontitis, is also linked to many systemic disorders due to its citrullination capability from a unique peptidyl arginine deiminase (PPAD). Protein citrullination is able to trigger an autoimmune response, increasing the severity of rheumatoid arthritis. The main objective of this study is to evaluate the inhibitory activity of Cratoxylym cochinchinense leaves extract towards the PPAD in vitro and in silico. Methanolic extract of Cratoxylum cochinchinense (CCM) was tested for total phenolic and flavonoid contents along with antioxidative assays. Inhibition of PPAD activities was conducted thereafter using recombinant PPAD in cell lysate. Phytocompounds postulated present in the CCM such as mangiferin, vismiaquinone A, δ-tocotrienol and α-tocotrienol and canophyllol were used as ligands in a simulated docking study against PPAD. Results obtained indicated high antioxidant potential in CCM while recording abundant phenolic (129.0 ± 2.5495 mg GA/g crude extract) and flavonoid (159.0 ± 2.1529 mg QE/g crude extract) contents. A dose-dependent inhibition of PPAD was observed when CCM was evaluated at various concentrations. CCM at 1 mg/mL exhibited citrulline concentration of 24.37 ± 3.25 mM which was 5 times lower than the negative control (114.23 ± 3.31 mM). Molecular docking simulation revealed that mangiferin and vismiaquinone A engaged in H-bonding and pi-pi interactions with important active site residues (Asp130, Arg152, Arg154 and Trp127) of PPAD and could be the potential phytochemicals that accounted for the inhibitory activities observed in the methanolic leaves extract. As such, CCM could be further explored for its therapeutic properties not only for periodontitis, but also for other systemic diseases like rheumatoid arthritis.

4.
Eur J Med Chem ; 188: 111983, 2020 Feb 15.
Article in English | MEDLINE | ID: mdl-31911292

ABSTRACT

Discovery and development of antimalarial drugs have long been dominated by single-target therapy. Continuous effort has been made to explore and identify different targets in malaria parasite crucial for the malaria treatment. The single-target drug therapy was initially successful, but it was later supplanted by combination therapy with multiple drugs to overcome drug resistance. Emergence of resistant strains even against the combination therapy has warranted a review of current antimalarial pharmacotherapy. This has led to the development of the new concept of covalent biotherapy, in which two or more pharmacophores are chemically bound to produce hybrid antimalarial drugs with multi-target functionalities. Herein, the review initially details the current pharmacotherapy for malaria as well as the conventional and novel targets of importance identified in the malaria parasite. Then, the rationale of multi-targeted therapy for malaria, approaches taken to develop the multi-target antimalarial hybrids, and the examples of hybrid molecules are comprehensively enumerated and discussed.


Subject(s)
Antimalarials/pharmacology , Artemisinins/pharmacology , Drug Discovery , Malaria/drug therapy , Paclitaxel/pharmacology , Quinolines/pharmacology , Animals , Antimalarials/chemistry , Artemisinins/chemistry , Drug Resistance/drug effects , Humans , Molecular Structure , Paclitaxel/chemistry , Quinolines/chemistry
5.
Molecules ; 24(20)2019 Oct 11.
Article in English | MEDLINE | ID: mdl-31614517

ABSTRACT

Human A3 adenosine receptor hA3AR has been implicated in gastrointestinal cancer, where its cellular expression has been found increased, thus suggesting its potential as a molecular target for novel anticancer compounds. Observation made in our previous work indicated the importance of the carbonyl group of amide in the indolylpyrimidylpiperazine (IPP) for its human A2A adenosine receptor (hA2AAR) subtype binding selectivity over the other AR subtypes. Taking this observation into account, we structurally modified an indolylpyrimidylpiperazine (IPP) scaffold, 1 (a non-selective adenosine receptors' ligand) into a modified IPP (mIPP) scaffold by switching the position of the carbonyl group, resulting in the formation of both ketone and tertiary amine groups in the new scaffold. Results showed that such modification diminished the A2A activity and instead conferred hA3AR agonistic activity. Among the new mIPP derivatives (3-6), compound 4 showed potential as a hA3AR partial agonist, with an Emax of 30% and EC50 of 2.89 ± 0.55 µM. In the cytotoxicity assays, compound 4 also exhibited higher cytotoxicity against both colorectal and liver cancer cells as compared to normal cells. Overall, this new series of compounds provide a promising starting point for further development of potent and selective hA3AR partial agonists for the treatment of gastrointestinal cancers.


Subject(s)
Gastrointestinal Neoplasms/drug therapy , Pyrimidinones/chemistry , Receptor, Adenosine A2A/genetics , Receptor, Adenosine A3/genetics , Adenosine A2 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/pharmacology , Animals , CHO Cells , Cell Proliferation/drug effects , Cricetinae , Cricetulus , Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/pathology , Humans , Indoles/chemical synthesis , Indoles/chemistry , Indoles/pharmacology , Models, Molecular , Piperazine/chemical synthesis , Piperazine/chemistry , Piperazine/pharmacology , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacology , Receptor, Adenosine A2A/chemistry , Structure-Activity Relationship
6.
PLoS One ; 13(1): e0188212, 2018.
Article in English | MEDLINE | ID: mdl-29304113

ABSTRACT

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra of the human brain, leading to depletion of dopamine production. Dopamine replacement therapy remains the mainstay for attenuation of PD symptoms. Nonetheless, the potential benefit of current pharmacotherapies is mostly limited by adverse side effects, such as drug-induced dyskinesia, motor fluctuations and psychosis. Non-dopaminergic receptors, such as human A2A adenosine receptors, have emerged as important therapeutic targets in potentiating therapeutic effects and reducing the unwanted side effects. In this study, new chemical entities targeting both human A2A adenosine receptor and dopamine D2 receptor were designed and evaluated. Two computational methods, namely support vector machine (SVM) models and Tanimoto similarity-based clustering analysis, were integrated for the identification of compounds containing indole-piperazine-pyrimidine (IPP) scaffold. Subsequent synthesis and testing resulted in compounds 5 and 6, which acted as human A2A adenosine receptor binders in the radioligand competition assay (Ki = 8.7-11.2 µM) as well as human dopamine D2 receptor binders in the artificial cell membrane assay (EC50 = 22.5-40.2 µM). Moreover, compound 5 showed improvement in movement and mitigation of the loss of dopaminergic neurons in Drosophila models of PD. Furthermore, in vitro toxicity studies on compounds 5 and 6 did not reveal any mutagenicity (up to 100 µM), hepatotoxicity (up to 30 µM) or cardiotoxicity (up to 30 µM).


Subject(s)
Adenosine A2 Receptor Antagonists/pharmacology , Antiparkinson Agents/pharmacology , Dopamine Agonists/pharmacology , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Receptor, Adenosine A2A/metabolism , Receptors, Dopamine D2/agonists , Receptors, Dopamine D2/metabolism , Adenosine A2 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/pharmacokinetics , Adenylyl Cyclase Inhibitors/chemistry , Adenylyl Cyclase Inhibitors/pharmacokinetics , Adenylyl Cyclase Inhibitors/pharmacology , Animals , Animals, Genetically Modified , Antiparkinson Agents/chemistry , Antiparkinson Agents/pharmacokinetics , CHO Cells , Cricetulus , Dopamine Agonists/chemistry , Dopamine Agonists/pharmacokinetics , Drosophila/genetics , Drosophila/metabolism , Drug Discovery , Drug Evaluation, Preclinical , Humans , Parkinsonian Disorders/drug therapy , Parkinsonian Disorders/genetics , Parkinsonian Disorders/metabolism , Piperazines/chemistry , Piperazines/pharmacokinetics , Piperazines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Radioligand Assay , Support Vector Machine
7.
J Mol Graph Model ; 76: 136-142, 2017 09.
Article in English | MEDLINE | ID: mdl-28728042

ABSTRACT

Conventional ligand and receptor similarity methods have been extensively used for exposing pharmacological relationships and drug lead discovery. They may in some cases neglect minor relationships useful for target hopping particularly against the remote family members. To complement the conventional methods for capturing these minor relationships, we developed a new method that uses a SLARC (Simultaneous Ligand And Receptor Clustering) 2D map to simultaneously characterize the ligand structural and receptor binding-site sequence relationships of a receptor family. The SLARC maps of the rhodopsin-like GPCR family comprehensively revealed scaffold hopping, target hopping, and multi-target relationships for the ligands of both homologous and remote family members. Their usefulness in new ligand discovery was validated by guiding the prospective discovery of novel indole piperazinylpyrimidine dual-targeting adenosine A2A receptor antagonist and dopamine D2 agonist compounds. The SLARC approach is useful for revealing pharmacological relationships and discovering new ligands at target family levels.


Subject(s)
Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/metabolism , Adenosine A2 Receptor Antagonists/chemistry , Binding Sites/physiology , Drug Discovery/methods , Humans , Ligands , Protein Binding/physiology , Receptor, Adenosine A2A/chemistry , Receptor, Adenosine A2A/metabolism , Receptors, Dopamine D2/agonists , Receptors, Dopamine D2/chemistry , Rhodopsin/chemistry , Rhodopsin/metabolism , Structure-Activity Relationship
8.
Bioorg Med Chem ; 22(5): 1751-65, 2014 Mar 01.
Article in English | MEDLINE | ID: mdl-24518296

ABSTRACT

In the present study, a molecular simplification approach was employed to design novel bicyclic pyrazolo[3,4-d]pyrimidine (PP) derivatives from tricyclic pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines (PTP) as promising human A3 adenosine receptor (hA3AR) antagonists. All the target compounds were synthesized using novel and efficient synthetic schemes and the structure-activity relationship studies of these PPs were explored through the synthesis of a series of PTP analogues with various substituents. Substituents with different lipophilicity and steric hindrance (e.g., alkyl and aryl-alkyl) functions were introduced at N(2) position of the pyrazole ring, while acyl groups with different electronic properties were introduced at C(6) position of the bicyclic nucleus to probe both electronic and positional effects. Most of the synthesized derivatives of the PP series presented good affinity at the hA3AR, as indicated by the low micromolar range of Ki values and among them, compound 63 with N(2) neopentyl substituents showed most potent hA3AR affinity with Ki value of 0.9 µM and high selectivity (hA1AR/hA3AR=>111 & hA2AAR/hA3AR=>111) towards other adenosine receptor subtypes. Interestingly, small isopropyl groups at N(2) position displayed high affinity at another receptor subtype (hA2AAR, e.g., compound 55, with Ki hA2AAR=0.8 µM), while they were less favorable at the hA3AR. Molecular docking analysis was also performed to predict the possible binding mode of target compounds inside the hA3AR and hA2AAR. Overall, PP derivatives represent promising starting points for new AR antagonists.


Subject(s)
Purinergic P1 Receptor Antagonists/chemistry , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Models, Molecular , Molecular Docking Simulation , Structure-Activity Relationship
9.
Chemistry ; 19(25): 8321-30, 2013 Jun 17.
Article in English | MEDLINE | ID: mdl-23613215

ABSTRACT

Human A3 adenosine receptor (A3AR) is a membrane-bound G protein-coupled receptor implicated in a number of severe pathological conditions, including cancer, in which it acts as a potential therapeutic target. To derive structure-activity relationships on pyrazolo-triazolo-pyrimidine (PTP)-based A3AR antagonists, we developed a new class of organometallic inhibitors through replacement of the triazolo moiety with an organoruthenium fragment. The objective was to introduce by design structural diversity into the PTP scaffold in order to tune their binding efficacy toward the target receptor. These novel organoruthenium antagonists displayed good aquatic stability and moderate binding affinity toward the hA3 receptor in the low micromolar range. The assembly of these complexes through a template-driven approach with selective ligand replacement at the metal center to control their steric and receptor-binding properties is discussed.


Subject(s)
Adenosine A3 Receptor Antagonists/chemical synthesis , Adenosine A3 Receptor Antagonists/pharmacology , Receptor, Adenosine A3/metabolism , Ruthenium Compounds/chemical synthesis , Ruthenium Compounds/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Models, Molecular , Molecular Structure , Protein Binding , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptor, Adenosine A3/chemistry , Structure-Activity Relationship
10.
Med Res Rev ; 33(2): 235-335, 2013 Mar.
Article in English | MEDLINE | ID: mdl-22095687

ABSTRACT

Adenosine is an ubiquitous local modulator that regulates various physiological and pathological functions by stimulating four membrane receptors, namely A(1), A(2A), A(2B), and A(3). Among these G protein-coupled receptors, the A(3) subtype is found mainly in the lung, liver, heart, eyes, and brain in our body. It has been associated with cerebroprotection and cardioprotection, as well as modulation of cellular growth upon its selective activation. On the other hand, its inhibition by selective antagonists has been reported to be potentially useful in the treatment of pathological conditions including glaucoma, inflammatory diseases, and cancer. In this review, we focused on the pharmacology and the therapeutic implications of the human (h)A(3) adenosine receptor (AR), together with an overview on the progress of hA(3) AR agonists, antagonists, allosteric modulators, and radioligands, as well as on the recent advances pertaining to the computational approaches (e.g., quantitative structure-activity relationships, homology modeling, molecular docking, and molecular dynamics simulations) applied to the modeling of hA(3) AR and drug design.


Subject(s)
Chemistry, Pharmaceutical/methods , Molecular Targeted Therapy/methods , Purinergic P1 Receptor Agonists/pharmacology , Receptor, Adenosine A3/chemistry , Receptor, Adenosine A3/drug effects , Animals , Brain Diseases/diagnosis , Brain Diseases/drug therapy , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/drug therapy , Drug Design , Humans , Inflammation/diagnosis , Inflammation/drug therapy , Receptor, Adenosine A3/metabolism , Sensitivity and Specificity , Structure-Activity Relationship
11.
Bioorg Med Chem ; 19(20): 6120-34, 2011 Oct 15.
Article in English | MEDLINE | ID: mdl-21908194

ABSTRACT

In an attempt to study the optimal combination of a phenyl ring at the C(2)-position and different substituents at the N(5)- and N(8)-positions towards the selective modulation of human A(3) adenosine receptors (hA(3)AR), we synthesized a new series of 2-para-(un)substituted-phenyl-pyrazolo-triazolo-pyrimidines bearing either a methyl or phenylethyl at N(8) and chains of variable length at N(5). Through biological evaluation, it was found that the majority of the compounds had good affinities towards the hA(3)AR in the low nanomolar range. Compound 16 possessed the best hA(3)AR affinity and selectivity profile (K(i)hA(3)=1.33 nM; hA(1)/hA(3)=4880; hA(2A)/hA(3)=1100) in the present series of 2-(substituted)phenyl-pyrazolo-triazolo-pyrimidine derivatives. In addition to pharmacological characterization, a molecular modeling investigation on these compounds further elucidated the effect of different substituents at the pyrazolo-triazolo-pyrimidine scaffold on affinity and selectivity to hA(3)AR.


Subject(s)
Pyrazoles/chemistry , Pyridines/chemistry , Receptor, Adenosine A3/chemistry , Triazoles/chemistry , Animals , CHO Cells , Cricetinae , Humans , Models, Molecular , Structure-Activity Relationship
12.
Bioorg Med Chem Lett ; 21(10): 2898-905, 2011 May 15.
Article in English | MEDLINE | ID: mdl-21511471

ABSTRACT

A ligand-based pharmacophore was obtained for a new series of 2-unsubstituted and 2-(para-substituted)phenyl-pyrazolo-triazolo-pyrimidines as potent human A(3) adenosine receptor antagonists. Through comparative molecular field analysis-based quantitative structure-activity relationship studies, structural features at the N(5)-, N(8)- and C(2)-positions of the tricyclic nucleus were deeply investigated, with emphasis given to the unprecedentedly explored C(2)-position. The resulting model showed good correlation and predictability (r(2)=0.936; q(2)=0.703; r(pred)(2)=0.663). Overall, the contribution of steric effect was found relatively more predominant for the optimal interaction of these antagonists to the human A(3) receptor.


Subject(s)
Adenosine A3 Receptor Antagonists , Pyrazoles/chemistry , Pyrimidines , Triazoles/chemistry , Adenosine A3 Receptor Antagonists/chemistry , Adenosine A3 Receptor Antagonists/pharmacology , Humans , Models, Molecular , Molecular Structure , Protein Binding/drug effects , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/pharmacology , Quantitative Structure-Activity Relationship
13.
J Med Chem ; 54(3): 877-89, 2011 Feb 10.
Article in English | MEDLINE | ID: mdl-21214204

ABSTRACT

The structure-activity relationship (SAR) of 1,2,4-triazolo[1,5-a]-1,3,5-triazine derivatives related to ZM241385 as antagonists of the A(2A) adenosine receptor (AR) was explored through the synthesis of analogues substituted at the 5 position. The A(2A) AR X-ray structure was used to propose a structural basis for the activity and selectivity of the analogues and to direct the synthetic design strategy to provide access to solvent-exposed regions. Thus, we have identified a point of substitution for the attachment of solubilizing groups to enhance both aqueous solubility and physicochemical properties, maintaining potent interactions with the A(2A) AR and, in some cases, receptor subtype selectivity. Among the most potent and selective novel compounds were a long-chain ether-containing amine congener 20 (K(i) 11.5 nM) and its urethane-protected derivative 14 (K(i) 17.8 nM). Compounds 20 and 31 (K(i) 11.5 and 16.9 nM, respectively) were readily water-soluble up to 10 mM. The analogues were docked in the crystallographic structure of the hA(2A) AR and in a homology model of the hA(3) AR, and the per residue electrostatic and hydrophobic contributions to the binding were assessed and stabilizing factors were proposed.


Subject(s)
Adenosine A2 Receptor Antagonists/chemical synthesis , Triazines/chemical synthesis , Triazoles/chemical synthesis , Adenosine A2 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , Crystallography, X-Ray , HEK293 Cells , Humans , Hydrophobic and Hydrophilic Interactions , Models, Molecular , Protein Binding , Protein Conformation , Radioligand Assay , Solubility , Static Electricity , Structure-Activity Relationship , Triazines/chemistry , Triazines/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Water
14.
Int J Med Chem ; 2011: 480652, 2011.
Article in English | MEDLINE | ID: mdl-25954519

ABSTRACT

In the past few decades, medicinal chemistry research towards potent and selective antagonists of human adenosine receptors (namely, A1, A2A, A2B, and A3) has been evolving rapidly. These antagonists are deemed therapeutically beneficial in several pathological conditions including neurological and renal disorders, cancer, inflammation, and glaucoma. Up to this point, many classes of compounds have been successfully synthesized and identified as potent human adenosine receptor antagonists. In this paper, an overview of the structure-activity relationship (SAR) profiles of promising nonxanthine pyrazolo derivatives is reported and discussed. We have emphasized the SAR for some representative structures such as pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines; pyrazolo-[3,4-c] or -[4,3-c]quinolines; pyrazolo-[4,3-d]pyrimidinones; pyrazolo-[3,4-d]pyrimidines and pyrazolo-[1,5-a]pyridines. This overview not only clarifies the structural requirements deemed essential for affinity towards individual adenosine receptor subtypes, but it also sheds light on the rational design and optimization of existing structural templates to allow us to conceive new, more potent adenosine receptor antagonists.

15.
J Med Chem ; 53(8): 3361-75, 2010 Apr 22.
Article in English | MEDLINE | ID: mdl-20307065

ABSTRACT

Among the heterocyclic structures identified as potent human A(3) (hA(3)) adenosine receptor's antagonists, we have demonstrated that the new pyrazolo-triazolo-pyrimidines, bearing an aryl group in replacement of the C(2)-furyl ring, not only confer a good pharmacological profile (with significantly enhanced selectivity against other adenosine receptor subytpes) but also overcome the metabolic transformation of the furan ring into toxic intermediates. All the synthesized [2-(para-substituted) phenyl]-pyrazolo-triazolo-pyrimidines showed affinity at the hA(3) receptor in the low nanomolar range. The most potent derivative of the series presented better affinity and excellent selectivity (compound 31, K(i) hA(3) = 0.108 nM; hA(1)/hA(3) = 5200; hA(2A)/hA(3) = 7200), in comparison to the C(2)-furyl counterpart. A receptor-driven molecular modeling investigation, based on a recently proposed model of A(3) receptor derived from the crystallographic structure of human A(2A) receptor, has been carried out in order to support the experimental binding data and to justify the enhanced selectivity against the other receptor subtypes.


Subject(s)
Acetamides/chemical synthesis , Adenosine A3 Receptor Antagonists , Furans/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Triazoles/chemical synthesis , Acetamides/chemistry , Acetamides/pharmacology , Adenosine A1 Receptor Antagonists , Adenosine A2 Receptor Antagonists , Adenylyl Cyclases/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Furans/chemistry , Furans/pharmacology , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Models, Molecular , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Radioligand Assay , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacology
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