Synthesis of new fenmetazole analogues with potential mixed α2-adrenergic antagonistic activity and noradrenaline-uptake inhibiting properties

Abstract In the search for new antidepressants with a rapid onset of action, fenmetazole analogues, bearing a second phenyl ring in a position previously shown not to be detrimental to affinity and selectivity for the α 2 -adrenoreceptors, were synthesized in an attempt to combine NA-uptake inhibition and blockade of the α 2 -adrenoreceptors in the same molecule. Some of the new molecules showed enhanced affinity and selectivity for the α 2 -adrenoreceptors compared to fenmetazole. Surprisingly, introduction of a phenyl ring in the structure of fenmetazole changed the agonistic action of the parent compound toward the α 1 -adrenoreceptors into an antagonistic effect. However, none of the new derivatives showed in vitro NA-uptake inhibitory potency substantially different from the low activity of fenmetazole in this test.