ChemInform Abstract: 2‐Substituted Tryptamines: Agents with Selectivity for 5‐HT₆ Serotonin Receptors.

Abstract

Several 2-alkyl-5-methoxytryptamine analogues are prepared and screened as serotonin agonists. In particular, derivative (IX) binds with high affinity at human 5-HT 6 receptors and is a full agonist, at least as potent as serotonin, in activating adenylate cyclase. Replacing the 2-ethyl substituent with a phenyl group results in a compound that retain 5-HT 6 receptor affinity but lacks agonist character. -(GLENNON, RICHARD A.; LEE, MASE; RANGISETTY, JAGADEESH B.; DUKAT, MALGORZATA;

5‐HT6 antagonists as potential treatment for cognitive dysfunction

“…5) In an attempt to identify potent and selective 5-HT 6 ligands, Glennon [Abate et al, 2005;ChangFong et al, 2004;Glennon, 2003;Glennon et al, 1999Glennon et al, , 2000Kolanos et al, 2006;Lee et al, 2000Lee et al, , 2005Pullagurla et al, 2003Pullagurla et al, , 2004aPullagurla et al, ,b, 2005Sikazwe et al, 2006;Siripurapu et al, 2006;Tsai et al, 2000] took a different but logical approach starting with the natural ligand serotonin (5-HT) (1). Initial efforts were aimed at identification of agonists based on the rationale that 5-HT and the related natural ligand 5-methoxytryptamine (34) act as agonists at the 5-HT 6 receptor subtype.…”

Design, synthesis and pharmacological evaluation of conformationally restricted N-arylsulfonyl-3-aminoalkoxy indoles as a potential 5-HT6 receptor ligands

“…Among these reported 5-HT 6 R ligands, a few were reported with conformationally constrained features. There are reports by Glennon et al with fused tryptamine side chain in six member ring (fused cyclohexyl type) that makes it conformationally restricted, 14 viz., tetrahydrocarbazole derivatives (Compound 1 in Figure 1). Although there was change in their spatial orientations, the compounds were active towards 5-HT 6 R. Similarly, GSK and Wyeth (Compound 4 and 5 in Figure 1) also reported potent 5-HT 6 R ligands with fused indole scaffold 15,16 ; their focus also was mainly on side chain and indole template.…”

Design, synthesis and pharmacological evaluation of indolylsulfonamide amines as potent and selective 5-HT6receptor antagonists

“…As part of our own research program, we at Suven have designed and developed selective 5-HT 6 receptor antagonist compound SUVN-502 (structure not disclosed) which has completed phase I trials for cognitive impairment in schizophrenia and Alzheimer's disease 30 . N,N-dimethyl-2-(5-methoxy-1-phenylsufonyl-1H-indole-3-yl)ethylamine (MS-245, Figure 2) is a 5-HT 6 R antagonist reported by Glennon et al 31 in early 2000. Since then a lot of reports have been published regarding variations in N,N-dimethyl amino alkyl side chain on and around the indole nucleus and their affinity 21,32,33 ( Figure 2).…”