title: Novel 8-(furan-2-yl)-3-benzyl thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine-2(3H)-thione as selective adenosine A(2A) receptor antagonist.
abstract: Adenosine A(2A) receptor (A(2A)R) antagonists have emerged as potential drug candidates to alleviate progression and symptoms of Parkinson's disease (PD), and reduce the dopaminergic side effects. The synthesis of novel compound 8-(furan-2-yl)-3-benzyl thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine-2-(3H)-thione (BTTP) was carried out to evaluate the potential of BTTP as A(2A)R antagonist using SCH58261, a standard A(2A)R antagonist. The strong interaction of BTTP with A(2A)R (ΔG=-12.46kcal/mol and K(i)=0.6nM) in silico analysis was confirmed by radioligand receptor binding studies showing high affinity (K(i)=0.004nM) and selectivity with A(2A)R (A(2A)/A(1)=1155-fold). The effect of CGS21680 (selective A(2A)R agonist) induced cAMP concentration (0.1pmol/ml) in HEK293 cells was antagonized with BTTP (0.065pmol/ml) and SCH58261 (0.075pmol/ml). Furthermore, BTTP pre-treated (5, 10 and 20mg/kg) haloperidol-induced mice demonstrated significant attenuation in catalepsy and akinesia. BTTP induced elevation in the striatal dopamine concentration (2.90μM/mg of tissue) was comparable to SCH58261 (2.92μM/mg of tissue) at the dose of 10mg/kg. The results firmly articulate that BTTP possesses potential A(2A)R antagonist activity and can be further explored for the treatment of PD.
authors: Medicinal Chemistry Division, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, North Campus, Mall Road, Delhi 110007, India.
authors: Sandeep Kumar
authors: SK
authors: Barodia
authors: Chandra Bhushan
authors: CB
authors: Mishra
authors: Amresh
authors: A
authors: Prakash
authors: J B
authors: JB
authors: Senthil Kumar
authors: Namrata
authors: N
authors: Kumari
authors: Pratibha Mehta
authors: PM
authors: Luthra
mesh_terms: D000166:Acridines / Q000493:pharmacokinetics; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D002461:Cell Line, Transformed; D002739:Chloroquinolinols / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D010627:Phenethylamines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D043683:Receptors, Adenosine A2 / Q000378:metabolism*; D013997:Time Factors; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; C095678:9-(3-cyanophenyl)hexahydro-1,8-acridinedione; D000166:Acridines; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D002739:Chloroquinolinols; D018492:Dopamine Antagonists; D010627:Phenethylamines; D011743:Pyrimidines; D043683:Receptors, Adenosine A2; D014230:Triazoles; D014316:Tritium; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000242:Cyclic AMP; D000241:Adenosine; C011838:halquinol