2-Substituted tryptamines:: Agents with selectivity for 5-HT6 serotonin receptors

Several 2-alkyl-5-methoxytryptamine analogues were designed and prepared as potential 5-HT6 serotonin agonists. It was found that 5-HT6 receptors accommodate small alkyl substituents at the indole 2-position and that the resulting compounds can bind with affinities comparable to that of serotonin. In particular, 2-ethyl-5-methoxy-N,N-dimethyltryptamine (8) binds with high affinity at human 5-HT6 receptors (K-i = 16 nM) relative to 5-HT (K-i = 75 nM) and was a full agonist, at least as potent (8: K-act = 3.6 nM) as serotonin (K-act = 5.0 nM), in activating adenylate cyclase. Compound 8 displays modest affinity for several other populations of 5-HT receptors, notably h5-HT1A (K-i = 170 nM), h5-HT1D (K-i = 290 nM), and h5-HT7 (K-i = 300 nM) receptors, but is otherwise quite selective. Compound 8 represents the first and most selective 6-HT6 agonist reported to date. Replacing the 2-ethyl substituent with a phenyl group results in a compound that retains 5-HT6 receptor affinity (i.e., 10: K-i = 20 nM) but lacks agonist character. 2-Substituted tryptamines, then, might allow entry to a novel class of 5-HT6 agonists and antagonists.