The overall objectives of the research are to develop novel drugs with therapeutic potential for treating cocaine addiction, and dopamine-related diseases which would benefit from elevation of extracellular dopamine levels The drugs are inhibitors of dopamine and serotonin transporters, the targets of anti-depressant, anti-hyperactivity drugs and cocaine The biogenic amines transmitters led chemists to accept the need for an amine nitrogen in design of drugs targeted to transporters and receptors This premise was changed when we reported high affinity non-amines drugs targeted to dopamine and serotonin transporters (Madras et al , Synapse 24 340, 1996) We now report four novel findings with non-amines 1 It is feasible to develop highly selective non-amines as the 8-oxa non-amine O-1059 (IC50 4 59 nM ) was > 450-fold selective for the dopamine over the serotonin transporter; 2 Hydrogen bonding is not necessary for conferring high affinity as the 8-carba an a log of O-1059 displayed high affinity for the transporter (IC50 5 5 nM); 3 The binding domain of a non-amine [3H]O-1059 is virtually identical to that of the monoamine [3H]WIN 35,428 (CFT; 4 Non-amines can elevate extracellular dopamine levels above basal levels in rodent brain Non-amine dopamine transport inhibitors retain the properties of their amine nitrogen-bearing counterparts and represent a new class of drugs with therapeutic potential for neuropsychiatric disorders Further investigation of this class of compounds is warranted PUBLICATIONS Madras BK, Miller G , George S, O'Dowd B, Meltzer PC Non-amines a new generation of monoamine reuptake (dopamine, serotonin transporter) inhibitors Soc Neurosci Abstr 24; 278, 1998 Madras BK , Miller G, Fischman AJ, Bonab A, Meltzer PC Monoamine transporters; novel insights with novel nonamines Naunyn-Schmiedeberg's Arch Pharmacol 358 R 73, 1998
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