EMDT

Abstract: A population of 100 graphics models of the human 5-HT6 serotonin receptor was constructed based on the structure of bovine rhodopsin. The endogenous tryptamine-based agonist serotonin (5-HT; 1) and the benzenesulfonyl-containing tryptamine-derived 5-HT6 receptor antagonist MS-245 (4a) were automatically docked with each of the 100 receptor models using a genetic algorithm approach. Similar studies were conducted with the more selective 5-HT6 receptor agonist EMDT (5) and optical isomers of EMDT-related analog 8, as well as with optical isomers of MS-245 (4a)-related and benzenesulfonyl-containing pyrrolidine 6 and aminotetralin 7. Although associated with the same general aromatic/hydrophobic binding cluster, 5-HT (1) and MS-245 (4a) were found to preferentially bind with distinct receptor conformations, and did so with different binding orientations (i.e., poses). A 5-HT pose/model was found to be common to EMDT (5) and its analogs, whereas that identified for MS-245 (4a) was found common to benzenesulfonyl-containing compounds. Specific amino acid residues were identified that can participate in binding, and evaluation of a sulfenamide analog of MS-245 indicates for the first time that the presence of the sulfonyl oxygen atoms enhances receptor affinity. The results indicate that the presence or absence of an N1-benzenesulfonyl group is a major determinant of the manner in which tryptamine-related agents bind at 5-HT6 serotonin receptors.

Abstract: Serotonin 5-HT6 receptors have been implicated in the regulation of cognition, locomotion, and mood, but the elucidation of their functions is complicated by conflicting data using various animal models. Here, a systematic evaluation showed that autoradiographic binding with the selective 5-HT6 receptor antagonist [125I]SB-258585 was similar in marmosets and rats. In both species, [125I]SB-258585 binding was enriched in the caudate-putamen. Various recently developed agonists and antagonists toward 5-HT6 receptors exhibited similarities in their abilities to displace [125I]SB-258585 binding in marmosets and rats. The rank order of pEC50 values were as follows: (+)EMDT-CR = EMD386088>MS-245 = 5-HT>EMDT>>(−)EMDT-CR; and (+)EMDT-CR = EMD386088>5-HT = MS-245 = EMDT>>(−)EMDT-CR, in marmosets and rats, respectively. Unilateral 6-hydroxydopamine lesioning of dopaminergic axons caused a significant decrease of [125I]SB-258585 binding in the caudate-putamen of both marmosets and rats. Nonetheless, acute administration of the 5-HT6 receptor agonist EMDT to unilaterally 6-hydroxydopamine-lesioned rats, caused an induction of egr-1, homer, and enkephalin mRNAs in the dopamine-depleted hemisphere, indicating a supersensitization of 5-HT6 receptors following dopamine depletion. In conclusion, this study provides evidence for significant similarities in the distribution, level, pharmacology, and regulation of 5-HT6 receptors between rats and marmosets. J. Comp. Neurol. 519:1815–1827, 2011. © 2011 Wiley-Liss, Inc.

Abstract: Depression affects around 16% of the population at some point in their lives and major depressive disorder is a leading cause of disability worldwide. Depression is caused by an interaction of genetic and environmental factors, but the molecular and cellular mechanisms underlying its pathogenesis are not entirely clear. The “monoamine hypothesis” of depression, which involves imbalances in serotonergic, noradrenergic and possibly dopaminergic functions, has dominated notions and explanations of the pathophysiology of depression. Most clinically used antidepressants act by increasing the synaptic levels of these monoamines. While these treatments are beneficial in many cases, a large population of depressed patients do not respond, or respond suboptimal, to these current antidepressant treatments. There is accumulating evidence that depression is associated with impairments of synaptic plasticity, dendritic arborization and cell proliferation/survival in hippocampus and frontal cortex and normalization of these processes could lead to antidepressant responses. The neurochemical mechanisms underlying these functional and structural impairments are poorly understood, but appear to involve changes in glutamate neurotransmission, neuropeptides, neurotrophins and intracellular signaling cascades. The present studies used biochemical and behavioural techniques and found that the atypical antidepressant, tianeptine, which is a serotonin reuptake enhancer, increased phosphorylation of the GluA1 subunits of AMPA glutamate receptors both in brain slices and in intact animals. Antidepressant and stimulatory behavioral responses to tianeptine were attenuated in mice bearing point mutations at Ser-/Ser-GluA1. Acute elevated platform stress, known to inhibit synaptic plasticity in hippocampal→frontal cortex neurotransmission, was found to downregulate a putative BDNF/MEK/MAPK signaling cascade in frontal cortex which could be counteracted by tianeptine, imipramine and the glucocorticoid receptor antagonist mifepristone. The serotonin receptors mediating the antidepressant effects of serotonin reuptake inhibitors, the currently most prescribed class of antidepressants, are not fully understood. Here, it is reported blockade of 5-HT6 receptors with the antagonist SB271046 counteracts the potentiating actions of fluoxetine on cortical phospho-Ser-GluA1 and reduces its antidepressant-like behavioral action. Moreover, the 5-HT6 receptor agonist EMDT mimics antidepressant-like biochemical and behavioral effects of fluoxetine. In conclusion, these studies have shown that the atypical antidepressant tianeptine can potentiate signaling cascades associated with synaptic plasticity and add further evidence that tianeptine acts as an enhancer of AMPA glutamate transmission. These studies also suggest, for the first time, a role for 5-HT6 receptors in mediating antidepressant responses. List of Publications I. Svenningsson P, Bateup H, Qi H, Takamiya K, Huganir RL, Spedding M, Roth BL, McEwen BS and Greengard P. (2007) Involvement of AMPA receptor phosphorylation in antidepressant actions with special reference to tianeptine. European Journal of Neuroscience. 26:3509-3517. II. Qi H, Zhang X, Delagrange P, Spedding M and Svenningsson P. Tianeptine increases phosphorylation of AMPA receptors and potentiates MAPK signalling. Manuscript. III. Qi H, Mailliet F, Spedding M, Rocher C, Zhang X, Delagrange P, McEwen B, Jay TM and Svenningsson P. (2009) Antidepressants reverse the attenuation of the neurotrophic MEK/MAPK cascade in frontal cortex by elevated platform stress; reversal of effects on LTP is associated with GluA1 phosphorylation. Neuropharmacology. 56:37-46. IV. Mailliet F, Qi H, Rocher C, Spedding M, Svenningsson P and Jay TM. (2008) Protection of stress-induced impairment of hippocampal/prefrontal LTP through blockade of glucocorticoid receptors: Implication of MEK signaling. Experimental Neurology. 211:593-596. V. Svenningsson P, Tzavara ET, Qi H, Carruthers R, Witkin JM, Nomikos GG and Greengard P. (2007) Biochemical and behavioral evidence for antidepressant-like effects of 5-HT6 receptor stimulation. Journal of Neuroscience. 27:4201-4209. Additional publications during PhD studies I. Smith DG, Qi H, Svenningsson P, Wade M, Davis RJ, Gehlert DR and Nomikos GG. (2008) Behavioral and biochemical responses to d-amphetamine in MCH1 receptor knockout mice. Synapse. 62:128-136. II. Warner-Schmidt JL, Flajolet M, Maller A, Chen EY, Qi H, Svenningsson P and Greengard P. (2009) Role of p11 in cellular and behavioral effects of 5-HT4 receptor stimulation. Journal of Neuroscience. 29:19371946. CONTENTS