Medicinal Chemistry Driven Approaches Toward Novel and Selective Serotonin 5-HT 6 Receptor Ligands

Department of Medicinal Chemistry, Laboratorios Dr. Esteve S.A., Av. Mare de Déu de Montserrat 221, 08041 Barcelona, Spain.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 04/2005; 48(6):1781-95. DOI: 10.1021/jm049615n
Source: PubMed


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.

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    • "Capitalising on this therapeutic mechanism, Arena's 5-HT 2C R agonist lorcaserin (Belviq) was launched in the USA in the summer of 2013 for obesity treatment. However, 5-HT 6 R antagonists have also been demonstrated to reduce food intake and body weight gain in comparable proportions to 5-HT 2C R agonists in preclinical studies [9] [10] [22] [25] and represent a further opportunity for obesity treatment drug development. However, the physiological mechanism through which 5-HT 6 R antagonists reduce food intake, achieved via advanced satiety, reduced hunger, induction of nausea, reduced hedonic properties, or induction of behaviours that interfere with feeding (e.g. "
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    ABSTRACT: The central 5-hydroxytryptamine (5-HT; serotonin) system is well established as an important regulator of appetite and continues to remain a focus of obesity research. While much emphasis has focussed on the 5-HT2C receptor (5-HT2CR) in 5-HT's anorectic effect, pharmacological manipulation of the 5-HT6 receptor (5-HT6R) also reduces appetite and body weight and may be amenable to obesity treatment. However, the neurological circuits that underlie 5-HT6R-induced hypophagia remain to be identified. Using c-fos immunoreactivity (FOS-IR) as a marker of neuronal activation, here we mapped the neuroanatomical targets activated by an anorectic dose of the 5-HT6R antagonist SB-399885 throughout the brain. Furthermore, we quantified SB-399855 activated cells within brain appetitive nuclei, the hypothalamus, dorsal raphe nucleus (DRN) and nucleus of the solitary tract (NTS). Our results reveal that 5-HT6R antagonist-induced hypophagia is associated with significantly increased neuronal activation in two nuclei with an established role in the central control of appetite, the paraventricular nucleus of the hypothalamus (PVH) and the NTS. In contrast, no changes in FOS-IR were observed between treatment groups within other hypothalamic nuclei or DRN. The data presented here provide a first insight into the neural circuitry underlying 5-HT6R antagonist-induced appetite suppression and highlight the PVH and NTS in the coordination of 5-HT6R hypophagia.
    Behavioural brain research 02/2014; 266(100). DOI:10.1016/j.bbr.2014.02.018 · 3.03 Impact Factor
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    • "The 5-HT 6 receptor has also been implicated in the regulation of memory processes (for a review see ; Fone et al. 2008) and the acute pro-cognitive activity of several 5-HT 6 receptor antagonists has been described in novel object discrimination (Hirst et al. 2006; King et al. 2004a, b; Lieben et al. 2005; Schreiber et al. 2007; Woolley et al. 2003), social recognition (Mitchell et al. 2006; Schreiber et al. 2007), autoshaping (Meneses 2001b; Perez-Garcia and Meneses 2005; Schreiber et al. 2007), Morris water maze (Hirst et al. 2006; Rogers and Hagan 2001; Stean et al. 2002; Woolley et al. 2001) and passive avoidance tasks (Foley et al. 2004; Schreiber et al. 2007). It is therefore an apparent paradox that E-6801, a full 5-HT 6 receptor agonist in in vitro studies (Holenz et al. 2005; Romero et al. 2006, 2007), caused a dose-related restoration of natural "
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    ABSTRACT: In rats, 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists improve learning and memory, but the effects of agonists are poorly defined. This study investigated the effects of 5-HT(6) receptor agonists and antagonists on a rodent model of recognition memory. Selective 5-HT(6) receptor agonists and antagonists were administered either alone, after a scopolamine-induced impairment, or combined with sub-effective doses of the acetylcholinesterase inhibitor, donepezil, or the glutamate NMDA receptor antagonist, memantine, in a novel object discrimination paradigm in adult rats. After a 4-h inter-trial delay to induce natural forgetting, vehicle-treated rats spent an equivalent time exploring novel and familiar objects during the choice trial. The 5-HT(6) receptor agonists, E-6801 (1.25-10 mg/kg i.p.) and EMD-386088 (5-10 mg/kg i.p.), and antagonists, SB-271046 and Ro 04-6790 (5 and 10 mg/kg), along with donepezil (0.1-3 mg/kg) and memantine (5-20 mg/kg) all produced significant and mostly dose-dependent increases in novel object exploration, indicative of memory enhancement. Furthermore, sub-effective doses of E-6801 (1 mg/kg) when co-administered with either SB-271046 (3 mg/kg), donepezil (0.1 mg/kg) or memantine (5 mg/kg), and EMD-386088 (2 mg/kg) co-administered with SB-271046 (3 mg/kg) also significantly enhanced object-recognition memory. Additionally, using a 1-min inter-trial delay, E-6801 (2.5 and 5 mg/kg) was as effective as donepezil (0.3 and 1 mg/kg) in reversing a scopolamine-induced (0.5 mg/kg) impairment in object recognition. This is the first study to demonstrate that E-6801, a potent 5-HT(6) receptor agonist, improves recognition memory by combined modulation of cholinergic and glutamatergic neurotransmission.
    Psychopharmacology 02/2011; 213(2-3):413-30. DOI:10.1007/s00213-010-1854-3 · 3.88 Impact Factor
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    • "Amine at 1-Position and a Sulfonamido Group at 4-, 5-, 6-, or 7-Position (Fig. 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 "
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    ABSTRACT: Among the potential therapeutic targets for the development of cognitive enhancers for AD and schizophrenia, the 5-HT6 receptor is of especial interest based on its localization, pharmacology, and recent behavioral data showing that 5-HT6 receptor blockade improves cognition in a number of rodent behavioral models. It is localized almost exclusively in the CNS, in areas important for learning and memory, while atypical antipsychotics and tricyclic antidepressants bind with high affinity to this target. 5-HT6 receptor antagonism enhances neurotransmission at cholinergic and glutamatergic neurons, as well as in other pathways. 5-HT6 antagonist medicinal chemistry and potential therapeutic applications for treatment of cognitive dysfunction is broadly reviewed. Drug Dev Res 70, 2009 © 2009 Wiley-Liss, Inc.
    Drug Development Research 03/2009; 70(2):145 - 168. DOI:10.1002/ddr.20293 · 0.77 Impact Factor
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