Author Topic: 2-Substituted Tryptamines; [...]  (Read 4217 times)

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2-Substituted Tryptamines; [...]
« on: March 23, 2003, 03:30:00 PM »
[...] Agents with Selectivity for 5-HT6 Serotonin

J. Med. Chem.; (Article); 2000; 43(5); 1011-1018

Richard A. Glennon,*,† Mase Lee,† Jagadeesh B. Rangisetty,† Malgorzata Dukat,† Bryan L. Roth,‡
Jason E. Savage,‡ Ace McBride,‡ Laura Rauser,‡ Sandy Hufeisen,‡ and David K. H. Lee§

Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298,
Departments of Biochemistry, Psychiatry, and Neurosciences, School of Medicine, Case Western Reserve University,
Cleveland, Ohio 44106, and Allelix Biopharmaceuticals, Mississauga, Ontario L4V 1V7, Canada

Abstract: 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.