P-98

2-5-Disubstituted tryptamines as selective

serotonin 5-HT6 receptor agonists
Annalida Bedini1,Tomaso Guidi1, Gilberto Spadoni1, Giorgio Tarzia1, Patrizia Minetti2,
Maria A. Di Cesare2, Paolo Carminati2
1
Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Urbino "Carlo
Bo", Piazza Rinascimento 6, I-61029 Urbino, Italy, 2Sigma-Tau Industrie Farmaceutiche
Riunite spa, Via Pontina Km 30,400, 00040 Pomezia, Italy.
Presenting author: gat@uniurb.it

5-HT6 serotonin receptors represent one of the seven major families of serotonin receptors
(5-HT1–5-HT7).[1] Its unique distribution in the brain and high affinity for therapeutic
antipsychotics and antidepressants suggests a possible role of the 5-HT6 receptor in CNS
disorders. Along with this, several studies have been published reporting an association of 5-
HT6 receptors with depression, psychosis, cognition, and appetite.[2] Nevertheless, the exact
(functional) role of the receptor in these indications has still to be ascertained.
During the past decade, considerable research efforts have been directed towards the
identification of selective 5-HT6 receptor modulators as tools for studying the receptor and as
potential therapeutic agents, allowing the identification of some interesting 5-HT6R
antagonists. [3] However, identification of selective 5-HT6 receptor agonists has proven very
challenging. One of the few agonists reported, 2-ethyl-5-methoxy-N,N-dimethyltryptamine
[4] has 16 nM affinity for the 5-HT6 receptor but it is only 10-, 20-, and 30-fold selective
over 5-HT1A, 5-HT1D, and 5-HT7 receptors, respectively.
In this report, we communicate the 2,5-disubstituted-tryptamines biochemical features
towards 5HT6 receptor. The 5-halo-2-alkyl derivatives (II) [5] were found to bind at 5-HT6
receptor with affinity about 3-fold less than that of serotonin (Ki 87 nM), and they behaved
as agonists with a potency higher or comparable to that of serotonin. It has also been found
that two compounds, ST1936 and ST2253, displayed reasonable selectivity for 5-HT6 over
other serotonin subtypes examined. Further, selected compounds (10-5M) examined at
different receptors population have not displayed any significant effect.

NR3R4 N(CH3)2

R1 X

R2 R2
N N
H X = Cl, Br
H
(I) (II) R2 = Me, Et

[1] Hoyer, D; Hannon, J P; Martin, G R. Pharmacol. Biochem. Behav. 2002; 71: 533.
[2] Woolley, M L; Marsden, C A; Fone, K C F. Curr. Drug Top. 2004; 3: 59.
[3] Holenz, J; Mercé, R; Diaz, J L. et al. J. Med. Chem. 2005; 48: 1781.
[4] Glennon, R A; Lee, M; Rangisetty, J B. et al. J. Med. Chem. 2000; 43: 1011.
[5] Di Cesare M A; Minetti, P; Tarzia, G; Spadoni, G. PCT Int. Appl. WO 2003000252,
2003 January 03.