AROMATIC AND AMINE SUBSTITUENT EFFECTS ON THE APPARENT LIPOPHILICITIES OF N-[(2-PYRROLIDINYL)METHYL]-SUBSTITUTED BENZAMIDES

Lipophilic properties of 92 dopamine D-2 receptor antagonists belongin g to the substituted benzamide class of compounds (orthopramides and m ethoxysalicylamides) were determined by octadecylsilane reversed-phase HPLC. The apparent lipophilicity at pH 7.5 (log k(w)) was obtained fr om the chromatographic capacity factors in 0.02 M 3-(morpholino)propan esulfonic acid (MOPS) buffer at various concentrations of methanol. Th e experimental log k(w) values were validated by comparison with the a pparent octanol-water partitioning (log P-app) of 15 compounds of low to medium lipophilicity. The global lipophilicity of the neutral molec ule (log k(w)(o)) was obtained by correcting for ionization of the ami ne and the phenol, using known relationships for the effects on the pK (a) (where K-a is the dissociation constant) of aromatic and aliphatic substituents. Multiple regression analysis showed that log k(w)(o) ca n be expressed as the sum of pi contributions and a cross correlation term (Sigma rho sigma) for interactions between the aromatic substitue nts. Comparison between the methoxysalicylamide (raclopride) series an d the orthopramide (sulpiride) series demonstrated that an aromatic 6- hydroxy group increased log k(w) 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 k (w) 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 intramolecularly hydrogen bond with the amide carbonyl group. Introduc tion of an additional ortho-methoxy substituent had the opposite effec t because the resulting steric hindrance prevents the amide moiety fro m adopting a coplanar conformation with the benzene ring. The presence of a substituent in the aromatic 3-position lowered log k(w) by 0.3 v ia a combination of steric and electronic influences on the adjacent 2 -methoxy group, causing a weakening of the hydrogen bond between the a mide and the oxygen atom of the 2-methoxy group. As a result, halogen and alkyl substituents in the 3-position increase the apparent lipophi licity only half that of similar substituents in the 5-position. Subst itution with omega-fluoroalkoxyl groups in the aromatic 2- and 3-posit ions and with omega-fluoroalkyl groups in the 5-position reduced lipop hilicities by 0.5 as compared with the corresponding desfluoro derivat ives, thereby making them equivalent to an alkyl derivative with one l ess carbon atom in the chain. In contrast, substitution on the pyrroli dine nitrogen atom with a 2-fluoroethyl or a 3-fluoropropyl group prod uced compounds with apparent lipophilicities similar to 1.5 and simila r to 0.5 higher, respectively, than those of the corresponding N-ethyl derivatives. These effects result from a fluorine-induced decrease of the basicity of the amine. With these relationships, the apparent lipo philicities at pH 7.4 were predicted for a series of recently develope d benzamide radioligands to evaluate their utility as single photon em ission computed topography and positron emission topography imaging ag ents of the dopamine D-2 receptor in the human brain.