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

In the search for novel serotonin receptor ligands, a series of 5-thiazolyl-N,N-dimethyltryptamine derivatives was synthesized which exhibited high affinity binding to 5-HT1A, 5-HT1B, and 5-HT1D receptors and the functional characteristics of receptor agonists. One member, 5-(4-anilinomethyl-2-thiazolyl)-N,N-dimethyltryptamine (CP-110,330), was found also to be a potent and selective inhibitor of dopamine uptake in rat striatal synaptosomes. This activity was confirmed by its potent displacement 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 activity was obtained when the thiazole C4 substituent consisted of phenyl with a 2-atom spacer. The potent effect of these 5-HT1 receptor ligands on dopamine uptake can be rationalized by the observation that the flexibility of these tryptamine molecules allows the superimposition of the phenyl ring and amino group of the side chain with the corresponding moieties of tametraline, a known catecholamine uptake inhibitor of fixed conformation. A related compound, 3-(R-N-methyl-2-pyrrolidinylmethyl)-5-(4-benzyl-2-thiazolylamino)- 1H-indole (CP-146,662) showed similar potent binding affinity to 5-HT1 receptors and the dopamine transporter. Compounds with this dual serotonergic and dopaminergic activity may have utility as antidepressant agents. As potent dopamine uptake inhibitors, they may also have application in the treatment of cocaine addiction. (C) 1994 Wiley-Liss, Inc.