Medicinal Chemistry Driven Approaches Toward Novel and Selective Serotonin 5-HT₆Receptor Ligands

Abstract

Based on a medicinal chemistry guided hypothetical pharmacophore model, novel series of indolyl sulfonamides have been designed and prepared as selective and high-affinity serotonin 5-HT(6) receptor ligands. Furthermore, based on a screening approach of a discovery library, a series of benzoxazinepiperidinyl sulfonamides were identified as selective 5-HT(6) ligands. Many of the compounds described in this paper possess excellent affinities, displaying pK(i) values greater than 8 (some even >9) and high selectivities against a wide range (>50) of other CNS relevant receptors. First, structure-affinity relationships of these ligands are discussed. In terms of functionality, high-affinity antagonists, as well as agonists and even partial agonists, were prepared. Compounds 19c and 19g represent the highest-affinity 5-HT(6) agonists ever reported in the literature. These valuable tool compounds should allow for the detailed study of the role of the 5-HT(6) receptor in relevant animal models of disorders such as cognition deficits, depression, anxiety, or obesity.

5‐HT6 antagonists as potential treatment for cognitive dysfunction

“…Holenz and coworkers independently discovered a similar class of 5-sulfonamidoindole derivatives 79-83 with the guide of a hypothetical model based on several known 5-HT 6 ligands [Holenz et al, 2005]. Potent 5-HT 6 agonists and antagonists were identified within the same chemical series.…”

“…11) Holenz and coworkers reported a series of indole derivatives with a basic amine at the 1-position of an indole template and with a sulfonamido group at the 4-, 5-, 6-, or 7-position (136-147) [Holenz et al, 2005;Merce et al, 2005a-d]. From the limited data reported, there was no clear trend in terms of the optimal sulfonamido position by the receptor although it seemed that 4-and 5-positions were slightly preferred over 6-and 7-positions.…”

Palladium-catalyzed amination of quinaldine-5-triflate

“…When using K 3 PO 4 or NaOt-Bu the reaction was slow and yielded poor conversion products (reactions 6 and 7). The coupling reaction with a solvent such as t-BuOH, 1,4-dioxane, and a mixture of toluene and t-BuOH was relatively slow and yielded some hydrolysis and decomposition of the starting compound (reactions [8][9][10]. Performing the amination reaction with xylene as a solvent resulted in an acceptable yield (reaction 13).…”

“…Selective 5-HT reuptake inhibitors are efficient antidepressants [1][2][3][4][5][6][7][8][9][10][11]. Among this group, heteroarylpiperazines, showed moderate to high affinity at the serotonin transporter and 5-HT 1A receptors.…”

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Abstract: Palladium-catalyzedaminationreactionsofquinolinetriflateandtheeffectofaPdcatalyst,itsligands,solvents,bases,andtemperaturewerestudied.Thismethodfacilitatedaneasierpathwayforthepreparationofaminoquinolinederivativesaspotentialprecursors ofnewserotoninergagents.

© Versita Warsaw and Springer-Verlag Berlin Heidelberg.

Keywords: Amination • Palladium-catalyst • Quinoline derivativesResearch article

1.IntroductionSelective 5-HT reuptake inhibitors are efficient antidepressants [1][2][3][4][5][6][7][8][9][10][11]. Among this group, heteroarylpiperazines, showed moderate to high affinity at the serotonin transporter and 5-HT 1A receptors.

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