A theoretical conformational study of substituted o-anisamides as models of a class of dopamine antagonists

Abstract

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.

Theoretical conformational studies of some dopamine antagonistic benzamide drugs: 3-pyrrolidyl- and 4-piperidyl derivatives

“…The methoxybenzamide moiety was constructed by standard geometry13 and fixed in a planar conformation as shown (VII, VIII), which corresponds to its energy minimum as demonstrated by preliminary calculations. 7 An alternate conformation is conceivable with the methoxy oxygen H bonding to the N+-H group of the side chain. Table I.…”

NMR Conformational Study of Aminoalkylbenzamides, Aminoalkyl‐o‐anisamides, and Metoclopramide, a Dopamine Receptor Antagonist

“…This appears to rule out any major conformational influence of solvation factors. Also, these results do not confirm the existence in solution of an intramolecular H-bond between N'-H and O=C as postulated in vacuum from PCILO calculations [5]. This semi-empirical method, however, is known to exaggerate attractive non-bonded interactions.…”

“…Theoretical conformational studies using the PCILO method [5] indicate for protonated aminoethyl-o -anisamides (e.g., metoclopramide) an energy difference of 10-1 5 kcal/mol between the preferred gauche-conformation and the trans-forms. The present work brings experimental evidence that in D,O-as well as in CDC1,-solution, protonated metoclopramide exists in gauche-and trans-conformations of equal energy.…”

“…The current evidence indicates that orthopramides act primarily as antagonists of a population of dopamine receptors not linked to adenylate cyclas~e (D-2 receptors) [ 1-41, To help unravel topographical elements of the D-2 receptor and the pharmacophore of orthopramides, we have calculated their conformational behaviour using a semi-empirical quantum mechanical method . The results indicate that aminoethyl derivatives such as metoclopramide (2) and tiapride (3) exist, without solvent interactions, in a folded (gauche) conformation 10-1 5 kcal/mol more stable than the extended (trans) conformation [5]. In 2-pyrrolidyl derivatives such as sulpiride (1) and 3-pyrrolidyl derivatives such as YM-09151-1 (4), the energy difference is decreased to 3-4 kcal/mol and 5-6 kcal/mol, respectively [6] [7].…”

Buspirone analogs. 1. Structure-activity relationships in a series of N-aryl- and heteroarylpiperazine derivatives

“…5,6 Such side effects are well-known and documented. 7,8 Earlier pharmacological studies of buspirone9,10 led to its evaluation in schizophrenia; however, the drug exhibited only transient activity even at high doses.11 Subsequent pharmacological investigation, directed at determining its mechanism of action, have demonstrated that while buspirone is without effect upon benzodiazepine binding and GABA binding or uptake, it may possess both agonist and antagonist activity at dopaminergic receptors.12"19 This profile of mixed agonist and antagonist properties may be relevant to buspirone's mechanism of anxioselective action in which no sedation, anticonvulsant, or muscle relaxant properties are associated with the drug.…”