The quantum mechanical PCILO method has been used to investigate the conformational behaviour of N‐(2‐aminoethyl)‐ and N‐(2‐dimethylaminoethyl)‐o‐anisamide, two model molecules of substituted benzamides. The molecules are shown to have only limited conformational freedom due to the presence of two intramolecular hydrogen bonds acting as conformational locks. The molecules in their preferred conformation are characterized by a distance between the centre of the aromatic ring and the nitrogen atom of almost 6 Å, i.e. almost 1 Å longer than in the fully extended dopamine conformers. Some implications at the receptor level of this topographical dissimilarity are discussed.
SummaryThe conformational behaviour of metoclopramide, a neuroleptic benzamide, and model compounds was investigated by 'H-NMR spectroscopy. An intramolecular amide-methoxy H-bond is shown to exist in CDC1,-solution, but not in D,O-solution, independently of the length and protonation state of the basic side-chain. This H-bond creates a virtual cycle which may be a key feature for the binding of neuroleptic benzamides to the dopamine receptor. The conformational behaviour of the aminoethyl side-chain is shown to be markedly condition-dependent. For nnetoclopramide and its analogues in their protonated form, the gauche-and trans-rotamers have identical energies in D,O-as well as in CDC1,-solutions. For the non-protonated molecules, the trans-rotamer is favoured in D,O-solution, while the gauche-rotamer is favoured in CDC1,-solution (AGO N 10.5lkcal/mol in both cases). The side-chain conformation of neuroleptic benzamides is discussed in terms of receptor affinity.
Summary N-Aminoalkylbenzamides and N-aminoalkyl-o-methoxybenzamides have been prepared and examined for their pK,, log P and dopamine receptor affinity. The pK, values range from ca. 7.5 for the derivatives having a one-C-atom side-chain, to ca.
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.
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