2-[(2-ethoxyphenoxy)-phenylmethyl]morpholine and nisoxetine

In a wide search program toward new, efficient, and fast-acting antidepressant drugs, we have prepared series of new compounds having an (aryl)(aryloxy)methyl moiety linked directly or through a methylene chain to different substituted and unsubstituted cycles (isoquinoline, piperazine, piperidine, tetrahydropyran, or cyclopentane). These compounds have been evaluated for their affinities for serotonin (5-HT) transporter (SERT) and 5-HT(1A) and 5-HT(2A) receptors. Racemic mixtures of 4-[(aryl)(aryloxy)methyl]piperidine derivatives showed much higher affinity values for SERT than fluoxetine and resulted in lack of affinity for 5-HT(1A) and 5-HT(2A) receptors. Some of these racemic mixtures were resolved to their enantiomers and tested for binding to norepinephrine (NE) transporter (NET), dopamine (DA) transporter (DAT), and alpha(2) receptor. Several of these enantiomers [(-)-15b, (-)-15j, (-)-15t, (+)-15u] displayed a dual binding profile with affinities for SERT and NET with K(i) < 25 nM and a NET/SERT ratio <10. Compound (-)-15j (coded as F-98214-TA for development studies) showed a dual binding profile with very high affinity values for SERT and NET (K(i) = 1.9 and 13.5 nM, respectively), and further pharmacological characterization is in progress for its evaluation as a antidepressant.

Topics: Adrenergic Uptake Inhibitors; Animals; Antidepressive Agents; Brain; Carrier Proteins; Fluoxetine; In Vitro Techniques; Male; Membrane Glycoproteins; Membrane Transport Proteins; Morpholines; Nerve Tissue Proteins; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Piperidines; Radioligand Assay; Rats; Rats, Wistar; Reboxetine; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Plasma Membrane Transport Proteins; Stereoisomerism; Structure-Activity Relationship; Symporters