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 (Ki) 16 nM) relative to 5-HT (Ki) 75 nM) and was a full agonist, at least as potent (8: Kact) 3.6 nM) as serotonin (Kact) 5.0 nM), in activating adenylate cyclase. Compound 8 displays modest affinity for several other populations of 5-HT receptors, notably h5-HT1A (Ki) 170 nM), h5-HT1D (Ki) 290 nM), and h5-HT7 (Ki) 300 nM) receptors, but is otherwise quite selective. Compound 8 represents the first and most selective 5-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: Ki) 20 nM) but lacks agonist character. 2-Substituted tryptamines, then, might allow entry to a novel class of 5-HT6 agonists and antagonists