AbstractA QSAR analysis of the [3H]spiperone binding affinity of 25 mono‐ and disubstituted salicylamides having F, Cl, Br, Me and Et substituents in the 3‐ and 5‐positions have been done with PLS (partial least squares in latent variables) method. Besides descriptors for size and lipophilicity, a large number of theoretically derived descriptors, i.e. polarizability, charge and molecular electrostatic potential (MEP), were used. The partial charges and the 3‐D MEPs were calculated using GAUSSIAN 80 at the STO‐3G level on model compounds lacking the pyrrolidine side‐chain. The MEPs at the van der Waals distance and at a larger distance corresponding to 3.0 Å from the aromatic plane were converted to point charges centered at the heavy atoms. The main component t1explains 71% of the observed variance in biological activity and with inclusion of two minor components t2and t3a total of 88% explained variance is obtained. The size, lipophilicity and electronics of the 3‐substituent are of major importance. The MEP descriptors at the 3.00 Å distance also influence the activity despite the fact that the gross behaviour of the 2‐D MEPs was highly variable with no apparent correlation with D‐2 activity. The present study does not fully support current MEP pharmacophores on closel