Antagonism of the 5-HT 6 receptor – Preclinical rationale for the treatment of Alzheimer's disease

Jong, Inge E.M. de; Mørk, Arne

doi:10.1016/j.neuropharm.2017.07.010

Cited by 66 publications

(58 citation statements)

References 163 publications

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“…The precise influence of 5-HTR subtypes deserves additional studies in view of their possible targeting in the clinic as cognitive enhancer [184]. It has been recently stressed out for 5-HT 4 R and 5-HT 6 R subtypes [137,185]. Several 5-HT 6 R antagonists have been tested in recent clinical trials in Alzheimer patients although the results were mitigated [186].…”

Section: Moodmentioning

confidence: 99%

Serotonin in Animal Cognition and Behavior

Bacqué-Cazenave

Bharatiya

Barrière

et al. 2020

IJMS

216

111

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Serotonin (5-hydroxytryptamine, 5-HT) is acknowledged as a major neuromodulator of nervous systems in both invertebrates and vertebrates. It has been proposed for several decades that it impacts animal cognition and behavior. In spite of a completely distinct organization of the 5-HT systems across the animal kingdom, several lines of evidence suggest that the influences of 5-HT on behavior and cognition are evolutionary conserved. In this review, we have selected some behaviors classically evoked when addressing the roles of 5-HT on nervous system functions.In particular, we focus on the motor activity, arousal, sleep and circadian rhythm, feeding, social interactions and aggressiveness, anxiety, mood, learning and memory, or impulsive/compulsive dimension and behavioral flexibility. The roles of 5-HT, illustrated in both invertebrates and vertebrates, show that it is more able to potentiate or mitigate the neuronal responses necessary for the fine-tuning of most behaviors, rather than to trigger or halt a specific behavior. 5-HT is, therefore, the prototypical neuromodulator fundamentally involved in the adaptation of all organisms across the animal kingdom.The organization of the 5-HT systems is completely different between species ranging from a limited number of cells in Aplysia or Drosophila (100 5-HT immunoreactive cells) to several thousand neurons in vertebrates. The variety and the heterogeneity of 5-HT neurons have been highlighted in vertebrates [7] as well as in invertebrates [8]. In general, the 5-HT systems in animals comprise 5-HT neurons, which share a particular shape made of thousands of varicosities, leading to the concept of volume transmission [9], and several 5-HT receptors (5-HTRs). In vertebrates, 5-HT neurons are localized in the midbrain raphe nuclei described as the B1-B9 cell groups [1,10]. The raphe pallidus, obscurus, and pontis form a caudal cluster (B1-B5), whereas the dorsal raphe and median raphe form a rostral cluster in the pons (B6-B9) [11]. The caudal raphe group projects to the spinal cord and the rostral group to the forebrain via an extensive and diffuse innervation. The dorsal raphe nucleus contains the highest number of 5-HT neurons and its anatomical sub-regions display some degrees of specific innervation of the forebrain [12][13][14]. The median and dorsal raphe nuclei receive excitatory and inhibitory inputs from most brain areas [15]. In crustaceans or insects, 5-HT neurons are widely present in each of the ventral cord ganglia, display large local ramifications that act in multiple neuropil areas, and some axonal branches form three pairs of rostrocaudal fibers [16][17][18][19]. Presumably, two of those fibers would project anteriorly and one posteriorly to the entire nervous system [20]. 5-HT neurons are often localized close to sensory integration input area in the brain of arthropods and some 5-HT cells in the abdominal ganglia of crayfish nerve cord are sensitive to the mechanical stimulation of abdominal segmental fringe hairs [21]. In cnidarians, 5-HT cells ...

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Section: Moodmentioning

confidence: 99%

Serotonin in Animal Cognition and Behavior

Bacqué-Cazenave

Bharatiya

Barrière

et al. 2020

IJMS

216

111

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“…Molecules 2019, 24, x; doi: www.mdpi.com/journal/molecules Furthermore, the above 20-year intensive search for 5-HT6R agents has not provided any compound that reached the pharmaceutical market. Among the most advanced ones investigated in potential usage for AD treatment, Idalopirdine (6) and Intepirdine (7) failed phase III of clinical trials, while SUVN-502 (8) gives a great hope because it has been successful in ongoing phase II trials ( Figure 1) [15]. An unsatisfactory "drugability," the so called "ADMET (absorption, distribution, metabolism, elimination, toxicity) profile," of the earlier investigated 5-HT6R ligands was one of the main reasons which disqualified them in the primary stages of drug R&D [16].…”

Section: Molecules 2019 24 X 3 Of 26mentioning

confidence: 99%

“…Thus, the ligands of 5-HT6R seem to be pivotal for the successful treatment of cognitive impairment. Predominantly, lines of evidence have indicated memory and learning ability improvement effects, useful in mild and moderate form of Alzheimer's disease (AD) and age-related cognitive decline as well as antidepressant-like, anxiolytic-like, and anti-obesity properties for 5-HT6R antagonists, while similar effects has also been confirmed for some 5-HT6R agonists [3,4,[6][7][8]. This paradox, although speaking in favor to 5-HT6R as a target, is still waiting to be explained.…”

Section: Introductionmentioning

confidence: 98%

Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

et al. 2019

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Though the 5-HT6 serotonin receptor is an important target giving both agonists and antagonists similar therapeutic potency in the treatment of topic CNS-diseases, no 5-HT6R ligand has reached the pharmaceutical market yet due to the too narrow chemical space of the known 5-HT6R agents and insufficient “drugability.” Recently, a new group of non-indole and non-sulfone hydantoin-triazine 5-HT6R ligands was found, where 3-((4-amino-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-yl)methyl)-5-methyl-5-(naphthalen-2-yl)imidazolidine-2,4-dione (KMP-10) was the most active member. This study is focused on wider pharmacological and “druglikeness” characteristics for KMP-10. A computer-aided insight into molecular interactions with 5-HT6R has been performed. “Druglikeness” was examined using an eight-test panel in vitro, i.e., a parallel artificial membrane permeability assay (PAMPA), and Caco-2 permeability-, P-glycoprotein (Pgp) affinity-, plasma protein binding-, metabolic stability- and drug–drug interaction-assays, as well as mutagenicity- and HepG2-hepatotoxicity risk tests. Behavioral studies in vivo, i.e., elevated plus-maze (EPM) and novel object recognition (NOR) tests, were performed. Extended studies on the influence of KMP-10 on rats’ metabolism, including biochemical tests, were conducted in vivo. Results indicated significant anxiolytic and precognitive properties, as well as some anti-obesity properties in vivo, and it was found to satisfy the “druglikeness” profile in vitro for KMP-10. The compound seems to be a good lead-structure and candidate for wider pharmacological studies in search for new CNS-drugs acting via 5-HT6R.

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“…Subgroup analyses should always be treated with caution, and previous trials based on hopeful hints in subgroups of early phase studies have failed 8. Even so, plausible biological mechanisms may explain why acting on both neurotransmitter systems might be effective,9 although it was also noted that idalopirdine, as a cytochrome P450 inhibitor, may simply be increasing the blood levels of co-administered donepezil 10…”

Section: Negative Drug Trialsmentioning

confidence: 99%