MCH1R antagonists have been used to treat several diseases, such as obesity, depression and anxiety. In this study, we have performed several pharmacophore-based CoMFA studies for a series of 2,4,6 substituted quinolines as potent antagonists of MCH1R. Significant statistical results were obtained (q2 = 0.78, r2 = 0.99), indicating the high internal consistency of the 3D model generated, as well as its predictive power for untested compounds. The 3D model was externally validated employing a test set and the predicted biological values showed good agreement with experimental results. Important insights on the molecular interactions between the studied ligands and the MCH1R receptor, inferred from the 3D contour maps, were obtained and can be useful for the design of new structurally related analogs with improved binding affinity.