NITROGEN-BASED DRUGS ARE NOT ESSENTIAL FOR BLOCKADE OF MONOAMINE TRANSPORTERS

In brain, monoamine transporters are principal targets of widely used therapeutic drugs including antidepressants, methylphenidate (Ritalin) , and the addictive drug cocaine. Without exception, these transport b locking agents contain an amine nitrogen. A prevalent view and unteste d premise is that an amine nitrogen is needed to bind to the same coun terion on the transporter as does the amine nitrogen of the monoamine neurotransmitter. We report that several compounds without nitrogen (8 -oxa-biyclo-3-aryl-[3.2.1] octanes, or aryloxatropanes) are active at monoamine transporters. One of these, tropoxane (O-914), bound with hi gh affinity to the dopamine (IC50: 3.35 +/- 0.39 nM), serotonin (IC50: 6.52 +/- 2.05 nM), and norepinephrine (IC50: 20.0 +/- 0.3 nM) transpo rters in monkey brain, the human striatal dopamine transporter (IC50: 5.01 +/- 1.74 nM), and blocked dopamine transport (IC50: 7.2 +/- 3.0 n M) in COS-7 cells transfected with the human dopamine transporter. The se unique compounds require a revision of current concepts of the drug binding domains on monoamine transporters, open avenues for discovery of a new generation of drugs and raise the issue of whether mammalian transporters and receptors may respond to, as yet, undiscovered non-a mine bearing neurotransmitters. (C) 1996 Wiley-Liss, Inc.