Dopamine is an abundant neurotransmitter in the brain, and acts as a regulator of many physiological functions in the central nervous system, such as motor activity, cognition, and positive reinforcement, and in the periphery, as a modulator of cardiovascular function, among others. Dopamine receptors belong to a superfamily of G protein-coupled receptors, and to date five sequences in the human body have been reported with various isoforms each. Disturbances in the dopaminergic systems are associated with several diseases, such as, for example, Parkinson's disease and schizophrenia. Since the disturbances affecting the locomotor activity are related to dopamine D2 receptors. Quantitative structure-activity relationship analysis in four-dimensional (4D-QSAR) studies were applied on a series of 73 tetracyclic tetrahydrofuran derivatives containing a substituted cyclic amine side chain with binding affinity towards dopamine D2 receptors. The 4D-QSAR models were developed using 60 compounds, the training set, and externally validated using 13 compounds, the test set. We tested three different alignments, and the Model 3, generated from Equation 3, showed the best statistical results, the same being chosen to represent the data set. The model developed in this work shows descriptors with important pharmacophoric groups for inhibiting dopamine D2 receptors, suggesting structural changes for new inhibitors.