Lipophilic properties of 92 dopamine D-2 receptor antagonists belonging to the substituted benzamide class of compounds (orthopramides and methoxysalicylamides) were determined by octadecylsilane reversed-phase HPLC. The apparent lipophilicity at pH 7.5 (log kw) was obtained from the chromatographic capacity factors in 0.02 M3-(morpholino)propanesulfonic acid (MOPS) buffer at various concentrations of methanol. The experimental log kw values were validated by comparison with the apparent octanol-water partitioning (log Papp) of 15 compounds of low to medium lipophilicity. The global lipophilicity of the neutral molecule (log kwo) was obtained by correcting for ionization of the amine and the phenol, using known relationships for the effects on the pKa (where Ka is the dissociation constant) of aromatic and aliphatic substituents. Multiple regression analysis showed that log kwo can be expressed as the sum of pi contributions and a cross correlation term (sigma rho sigma) for interactions between the aromatic substituents. Comparison between the methoxysalicylamide (raclopride) series and the orthopramide (sulpiride) series demonstrated that an aromatic 6-hydroxy group increased log kw by 0.4 in the 5-halogen series and by 0.8 in the 5-alkyl series, and that a 6-methoxy group decreased log kw by 0.5. These paradoxical effects can be explained by the masking of the polarity of the amide caused by the 6-hydroxy group forming an intramolecular hydrogen bond with the amide carbonyl group. Introduction of an additional ortho-methoxy substituent had the opposite effect because the resulting steric hindrance prevents the amide moiety from adopting a coplanar conformation with the benzene ring. The presence of a substituent in the aromatic 3-position lowered log kw by 0.3 via a combination of steric and electronic influences on the adjacent 2-methoxy group, causing a weakening of the hydrogen bond between the amide and the oxygen atom of the 2-methoxy group. As a result, halogen and alkyl substituents in the 3-position increase the apparent lipophilicity only half that of similar substituents in the 5-position. Substitution with omega-fluoroalkoxyl groups in the aromatic 2- and 3-positions and with omega-fluoroalkyl groups in the 5-position reduced lipophilicities by 0.5 as compared with the corresponding desfluoro derivatives, thereby making them equivalent to an alkyl derivative with one less carbon atom in the chain. In contrast, substitution on the pyrrolidine nitrogen atom with a 2-fluoroethyl or a 3-fluoropropyl group produced compounds with apparent lipophilicities approximately 1.5 and approximately 0.5 higher, respectively, than those of the corresponding N-ethyl derivatives.(ABSTRACT TRUNCATED AT 400 WORDS)