Basicity, Lipophilicity, and Lack of Receptor Interaction of N‐Aminoalkylbenzamides and N‐Aminoalkyl‐o‐anisamides as Model Compounds of Dopamine Antagonists

Abstract

N‐Aminoalkylbenzamides and N‐aminoalkyl‐o‐methoxybenzamides have been prepared and examined for their pKa, log P and dopamine receptor affinity. The pKa values range from ca. 7.5 for the derivatives having a one‐C‐atom side‐chain, to ca. 10.3 for the N‐aminobutyl derivatives. These variations with chain length are satisfactoryly explained by a field model. The variations in (log P)‐values as a function of chain length and substitution at the N‐atom indicate the involvement of proximity and conformational effects. The complete inability of the compounds to displace 3H‐spiperone and 3H‐sulpiride from their specific rat striatal binding sites demonstrates the critical role of adequate aromatic substitution at positions 4 and 5.

Preparation and Characterization of Aminated Carbon from a Single-Step Reaction

“…6−10.8 ,, and 10.9 52 are found for C3 and C6, respectively. Even more significant is the comparison with N -alkylbenzamides (PhCONH(CH 2 ) n NH 2 , n = 2−4) where protonation of unreacted terminal −NH 2 groups is characterized by p K b values that increase with increasing chain length, that is, p K b = 9.12 ( n = 2), p K b = 9.92 ( n = 3), and p K b = 10.34 ( n = 4) . The close correspondence of p K b = 9.92 with the experimental pH pzc of D3 (pH pzc = 9.6) can be considered to show that protonation involves comparable chemical states of −NH 2 groups in the model benzamide and in functional groups at the carbon surface.…”