DOPAMINE UPTAKE INHIBITORY ACTIVITY OF NOVEL TRYPTAMINE 5-HT, RECEPTOR LIGANDS

In the search for novel serotonin receptor ligands, a series of 5-thia zolyl-N,N-dimethyltryptamine derivatives was synthesized which exhibit ed high affinity binding to 5-HT1A, 5-HT1B, and 5-HT1D receptors and t he functional characteristics of receptor agonists. One member, -anili nomethyl-2-thiazolyl)-N,N-dimethyltryptamine (CP-110,330), was found a lso to be a potent and selective inhibitor of dopamine uptake in rat s triatal synaptosomes. This activity was confirmed by its potent displa cement of [H-3]N-(-1-[2-benzo(b)thiophenyl]cyclohexyl) (BTCP) binding to the dopamine transporter in striatal membranes. A limited structure -activity study indicated that optimal dopamine uptake blocking activi ty was obtained when the thiazole C4 substituent consisted of phenyl w ith a 2-atom spacer. The potent effect of these 5-HT1 receptor ligands on dopamine uptake can be rationalized by the observation that the fl exibility of these tryptamine molecules allows the superimposition of the phenyl ring and amino group of the side chain with the correspondi ng moieties of tametraline, a known catecholamine uptake inhibitor of fixed conformation. A related compound, pyrrolidinylmethyl)-5-(4-benzy l-2-thiazolylamino)- 1H-indole (CP-146,662) showed similar potent bind ing affinity to 5-HT1 receptors and the dopamine transporter. Compound s with this dual serotonergic and dopaminergic activity may have utili ty as antidepressant agents. As potent dopamine uptake inhibitors, the y may also have application in the treatment of cocaine addiction. (C) 1994 Wiley-Liss, Inc.