Advances toward New Antidepressants with Dual Serotonin Transporter and 5-HT_1A Receptor Affinity within a Class of 3-Aminochroman Derivatives. Part 2

Abstract

Novel compounds combining a 5-HT 1A moiety (3-aminochroman scaffold) and a 5-HT transporter (indole analogues) linked through a common basic nitrogen via an alkyl chain attached at the 1- or 3-position of the indole were evaluated for dual affinity at both the 5-HT reuptake site and the 5-HT 1A receptor. Compounds of most interest were found to have a 5-carbamoyl-8-fluoro-3-amino-3,4-dihydro-2 H-1-benzopyran linked to a 3-alkylindole (straight chain), more specifically substituted with a 5-fluoro (( R)-(-)- 35c), 5-cyano ((-)- 52a), or 5,7-difluoro ((-)- 52g). Several factors contributed to 5-HT 1A affinity, serotonin rat transporter affinity, and functional antagonism in vitro. Although most of our analogues showed good to excellent affinities at both targets, specific features such as cyclobutyl substitution on the basic nitrogen and stereochemistry at the 3-position of the chroman moiety seemed necessary for antagonism at the 5-HT 1A receptor. Branched linkers seemed to impart antagonism even as racemates; however, the potency of these analogues in the functional assay was not desirable enough to further pursue these compounds.

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

“…Lu AA21004 is a SERT inhibitor, a full 5-HT 1A receptor agonist, and a 5-HT 3A receptor antagonist that currently is in phase III clinical trials for treatment of depression (Bang- Andersen et al, 2011). Likewise, other companies have also pursued dual SERT and NET inhibitors and 5-HT 1A receptor agonists (Hatzenbuhler et al, 2006(Hatzenbuhler et al, , 2008. Other multiple target strategies for development of monoamine transporters inhibitors with additional activity as antidepressants (Millan, 2006(Millan, , 2009 include combined NRI activity and 5-HT 2A receptor antagonism (Heffernan et al, 2008), SSRI activity and neurokinin 1 receptor antagonists (Ryckmans et al, 2002a,b) or histamine H 3 receptor antagonist (Barbier et al, 2007).…”

Rhodium‐Catalyzed Asymmetric Hydrogenation of 3‐Benzoylaminocoumarins for the Synthesis of Chiral 3‐Amino Dihydrocoumarins

“…For example, the structural motif is found in a β‐lactamase enzyme inhibitor, [9a] and a platelet aggregation inhibitor [9b] . It can also be transformed to various bioactive molecules, such as the novel dopamine β‐hydroxylase inhibitor Etamicastat, [9c] the selective 5‐HT 1 A receptor antagonist Robalzotan, [9d] an anti‐breast cancer agent, [9e] and an immunomodulator [9f] (Figure 1). Therefore, the efficient synthesis of these types of compounds is greatly desired.…”

4WD to Travel Inside the 5-HT1A Receptor World

“…The hybridation between the chromane-based structure, present in 5-HT 1A R antagonists, and the 3-indolyl-alkylamine moiety, embedded in numerous SSRIs, leads to compounds with mixed profiles. 5-Carboxamide-8-fluoro derivatives as well as 5-carboxamide-8-des-fluoro analogues with proper N-alkyl chains display good affinities for both 5-HT 1A Rs and 5-HT reuptake site [48]. In particular, 114 (Figure 37) behaves as a very potent 5-HT 1A R antagonist and SSRI.…”