Quantitative structure activity relationship studies are indubitably of great importance in modern chemistry. In pursuit of better antihypertensive agents, QSAR studies were performed on a series of 48 N 6 -substituted adenosines analogs. The models were developed using multiple linear regression (MLR) and partial least square (PLS) with many descriptors like electronic, topological, and lipophilic. QSAR models were evaluated for statistical significance and predictive power. The MLR and PLS generated comparable results with good predictive ability and all the other statistical values such as r, r 2 , r cv 2 , F, and s values were 0.92, 0.84, 0.83, 61.74, 0.24, respectively, for MLR and r cv 2 and statistical significance values of 0.82 and 0.80, respectively, for PLS were satisfactory. The model indicates that the Verloop L, total lipole, VAMP nuclear energy, plays an important role in determining the antihypertensive activity of N 6 -substituted adenosine receptor agonists. The model developed in the present study will be useful in the design of more potent N 6 -substituted adenosine receptor agonists as antihypertensive agent.