N-Arylsulfonylindole Derivatives as Serotonin 5-HT₆Receptor Ligands

Abstract

A series of N(1)-arylsulfonyltryptamines were found to be potent ligands of the human serotonin 5-HT(6) receptor with the 5-methoxy-1-benzenesulfonyl analogue (19) having the highest affinity. Additionally, it was discovered that a group such as 3-(3-methoxybenzyl)-1,2,4-oxadiazol-5-yl in the 2-position of the indole ring (43) can replace the arylsulfonyl substituent in the 1-position with no loss of affinity. This suggested that the binding conformation of the aminoethyl side chain at this receptor was toward the 4-position of the indole ring and was supported by the fact that the 4-(aminoethyl)indoles (45) also displayed high affinity, as did the conformationally rigid 1,3,4,5-tetrahydrobenz[c,d]indole (49). Molecular modeling showed that 19, 43, and 45 all had low-energy conformers that overlaid well onto 49. Both 19 and 49 had good selectivity over other serotonin receptors tested, with 49 also showing excellent selectivity over all dopamine receptors. In a functional adenylate cyclase stimulation assay, 19 and 49 had no agonist activity, whereas 45 behaved as a partial agonist. Finally, it was shown that 19 had good activity in the 5-HT(2A) centrally mediated mescaline-induced head twitch assay, which implies that it is brain-penetrant.

Reversal of a cholinergic-induced deficit in a rodent model of recognition memory by the selective 5-HT6 receptor antagonist, Ro�04-6790

“…Research into the functional role of the receptor was initially hampered due to a lack of selective ligands and early studies made use of antisense oligonucleotides to reduce 5-HT 6 receptor expression (Bourson et al 1995;Bentley et al 1997;Yoshioka et al 1998;Hamon et al 1999;Otano et al 1999). However, recently a number of selective 5-HT 6 receptor antagonists have been characterized Bromidge et al 1999;Issac et al 2000;Lee et al 2000;Tsai et al 2000;Slassi et al 2000;Bös et al 2001;Russell et al 2001), providing more selective tools with which to probe the functional role of this receptor. To date, the receptor has been implicated in psychotic disorders (Monsma et al 1993;Roth et al 1994;Tsai et al 1999;Yu et al 1999;Pouzet et al 2002), affective disorders (Roth et al 1994;Yau et al 1997;Vogt et al 2000), anxiety (Yoshioka et al 1998;Hamon et al 1999;Otano et al 1999), epilepsy (Routledge et al 2000) and potentially the regulation of food consumption (Bentley et al 1997(Bentley et al , 1999bWoolley et al 2001), but the most compelling evidence suggests a role for the receptor in cognitive function.…”

Environmentally Friendly Synthesis of Indoline Derivatives using Flow‐Chemistry Techniques

“…The most promising results were achieved by Kulkarni et al, [50] who used an acid catalyst to protonate the indoles at the C3 position to disrupt the aromaticity and to generate an iminium ion, which could be hydrogenated under less harsh conditions. Nevertheless, the use of an acid as a catalyst [37,[51][52][53][54][55][56][57] raises further difficulties, such as polymerization caused by even weak electrophiles, as it is known that indoles are highly activated aromatic compounds. [58,59] Unfortunately, overhydrogenation also remained an issue in acidic media, and this resulted in the formation of significant amounts of byproducts (mainly octahydroindoles).…”

One-Pot N-Arylation of Indoles Directly from N-Arylsulfonylindoles via Consecutive Deprotection and SNAr Reactions with Activated Aryl Halides

“…[18][19][20][21] The arylsulfonyl groups are useful for protecting groups for the NH group of the indoles because of their robust behavior under a wide variety of reaction conditions. [22][23][24][25] Recently, many methods for the deprotection of N-tosylated indoles have been described, such as highly basic NaOH or KOH in alcohol, 26) tetra-n-butylammonium fluoride (TBAF) in refluxing tetrahydrofuran (THF), 27) and Mg in MeOH. 28) However, to the best of our knowledge, N-arylsulfonylindoles have never been used as latent indoles in the SNAr reactions with aryl halides to prepare N-arylindoles directly.…”