Synthesis and adenosine receptor binding studies of some novel triazolothienopyrimidines.
A new series of 5-alkyl/aryl-8,9-dimethyl/8,9,10,11-tetrahydro[1]benzothieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thiones (4a-k) have been synthesized through a facile cyclization reaction of 4-hydrazino-2-alkyl/aryl-5,6-dimethyl/5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidines (3a-k) using carbon disulphide under basic conditions. 4-Hydrazino-2-alkyl/aryl-5,6-dimethyl/5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidines (3a-k) were prepared by replacing the chloro group of 4-chloro-2-substituted-5,6-dimethyl/5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidines (2a-k) with hydrazine hydrate which were obtained by a known one-pot synthesis. The affinities of these compounds for adenosine A(1)/A(2A) receptors were determined at 1 microM concentration. The test compounds which exhibited more than 20% inhibition were selected and further screened at six different concentration levels to estimate their EC(50)/K(i) values. The most potent compounds in the series were 4c and 4d having an ethyl side chain at C(5) position with dimethyl and cyclohexyl substitution at the C(8)-C(9) positions, exhibiting K(i) values of 2.1 and 1.1 microM, respectively, at A(1)ARs. The SAR indicates that by increasing or decreasing the alkyl chain length at C(5) led to reduced affinity. The remaining aryl/arylalkyl derivatives of the series were inactive showing that a simple alkyl side chain at C(5) is necessary for these ligands to bind at A(1)ARs. However, none of the compounds showed inhibition on A(2A) receptors at 1 microM concentration indicating their selectivity. This communication describes the design, synthesis and evaluation of these new molecules.
Raghu Prasad
Mailavaram
M
Medicinal Chemistry Research Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal 506 009, AP, India. raghumrp@mailcity.com
Raghuram Rao
Akkinepally
A
Shanthan Rao
Pamulaparthy
P
Rajan
Kombu Subramanian
KS
Meena
Shanmugam
S
Madhavi
Kuchana
K
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D015195:Drug Design; D011485:Protein Binding; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043683:Receptors, Adenosine A2 / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism*
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D043682:Receptor, Adenosine A1; D043683:Receptors, Adenosine A2; D018047:Receptors, Purinergic P1; C476003:thienopyrimidine