Non-amines, drugs without an amine nitrogen, potently block serotonin transport: Novel antidepressant candidates?

The serotonin transporter (SERT) is a principal site of action of therapeut ic antidepressants in the brain. Without exception, these inhibitors of ser otonin transport contain an amine nitrogen in their structure. We previousl y demonstrated that novel compounds without an amine nitrogen in their stru cture (non-amines), blocked dopamine transport in cells transfected with th e human dopamine transporter. The present study investigated whether, in th e absence of an amine nitrogen, certain non-amines bind selectively to the SERT and block the transport of serotonin. At 10 muM concentration, select non-amines displayed no, or little, affinity for 9 serotonin, 5 dopamine, 7 adrenergic, 5 musearinic cholinergic, 3 opiate and histamine receptors. Th e affinities of non-amines for [H-3]citalopram binding sites on the SERT an d their potencies for blocking [H-3]serotonin transport were measured in cl oned human SERT stably or transiently expressed in HEK-293. Whether oxa- or carba-based, non-amines bound to [H-3]citalopram-labeled sites and blocked PHIserotonin transport in the low nanomolar range, at values equal to or h igher than those of some conventional antidepressants. A non-amine, 0-1809, was 99-fold more selective for the serotonin over the dopamine transporter . As substituents on the aromatic ring of non-amines confer high affinity f or the SERT, we investigated the hypothesis that aromatic-aromatic interact ions may contribute significantly to non-amine/transporter association. A S ERT mutant was produced in which a highly conserved aromatic amino acid, ph enylalanine, 548, was replaced by an alanine (F548A). Although the affiniti es of several non-amines were unchanged in the mutant SERT, the affinity of imipramine was decreased, revealing possible differences in amine and non- amine binding domains on the SERT. The similar affinities of non-amines and conventional antidepressant drugs for the SERT support the view that an am ine nitrogen is not essential for drugs to block serotonin transport with h igh affinity. Non-amines open avenues for developing a new generation of an tidepressants. (C) 2001 Wiley-Liss, Inc.