Conformational analysis of nisoxetine and fluoxetine, selective inhibitors of norepinephrine and serotonin reuptake: are conformational differences an explanation of neurotransmitter selectivity?

Low energy conformations and the pathways between them have been calculated for nisoxetine (N-methyl-3-phenyl-3-(o-methoxyphenoxy)-propylamine), (I), a selective inhibitor of neuronal reuptake of norepinephrine, and fluoxetine (N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine), (II), a selective inhibitor of neuronal reuptake of serotonin. Results are presented as a series of energy maps and ORTEP drawings. Conformational preferences of the protonated forms and preferred conformations in aqueous solution are also established. The CAMSEQ empirical potential method was used throughout. Both the nisoxetine and fluoxetine systems are shown to exhibit the known 'folded-extended' conformational preferences of the phenethylamines. It is suggested that the observed conformational variation between the two systems may play a role in the pharmacological differences between nisoxetine and fluoxetine.