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.