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  • Derivatives of M that possess

    2022-11-18

    Derivatives of (+)-M100907 that possess either an alkyne or an azide have been synthesized. The most active enantiomer was obtained by resolution of a relatively early intermediate in the synthesis. The ability of these 5046 to maintain 5-HTR antagonist properties as (+)-M100907 was demonstrated together with the ability to use dipolar cycloaddition between the alkyne and azide to link these molecules to form bivalent antagonists. The 1,2,3-triazole ring generated in the dipolar cycloaddition used to link to the M100907 derivatives does not interfere with the ability of the bivalent ligand to act as an antagonist. Thus, functional versions of M100907 have been synthesized with tethers possessing azides or alkynes, allowing the application of these molecules in the synthesis of dimeric ligands as well as conjugation of the 5-HTR antagonist to reporter molecules, such as fluorophores, for the study of GPCR dimerization and their role in signaling. Materials and methods
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    Introduction Synaptic plasticity, or the ability of neuronal connectivity to change over time, plays a crucial role in the ability of the nervous system to adjust responses to incoming sensory stimuli and store information for prolonged time periods (Bliss and Collingridge, 1993, Hebb, 2002, Martin and Morris, 2002). Two widely studied forms of synaptic plasticity are long-term potentiation (LTP) and long-term depression (LTD), which refer to long-lasting increases and decreases, respectively, in synaptic strength (Bennett, 2000, Malenka and Bear, 2004). The interest in LTP and LTD stems, at least in part, from considerable evidence that the synaptic and molecular mechanisms mediating LTP and LTD are similar or identical to those recruited during training and memory formation, indicating that LTP and LTD constitute important mechanism for behavioral plasticity in various animal species (Lynch, 2004, Martin and Morris, 2002, Massey and Bashir, 2007, Neves et al., 2008). LTP and LTD are readily induced at synapses throughout the forebrain, including the hippocampal formation, amygdala, striatum, and neocortex (Bennett, 2000, Malenka and Bear, 2004, Tsumoto, 1992). An important aspect of LTP is that the induction threshold, magnitude, and duration of synaptic potentiation are strongly influenced by the chemical milieu, particularly the levels of various neuromodulators such as acetylcholine (ACh), noradrenaline (NA), histamine, and serotonin (5-hydroxytryptamine, 5-HT; Dringenberg and Kuo, 2006, Gu, 2002, Kojic et al., 1997). Given that their release systematically changes over the sleep-wake cycle (Scammell et al., 2017), fluctuating levels of ACh, 5-HT, NA, and others likely play an important role in mediating the influence of waking and sleep states on the induction/encoding, consolidation, and elimination of synaptic plasticity and memory traces in neuronal circuits (Power, 2004). The role of neocortical 5-HT release in gating plasticity induction and maintenance has been extensively studied in the primary visual cortex (V1) of rodents. In slices obtained from kittens or adult rats, bath application of 5-HT can result in a pronounced facilitation of LTP at V1 synapses (Kojic et al., 1997, Kojic et al., 2000, Park et al., 2012), while 5-HT depletion has been shown to impair LTP induction, an effect that is mimicked by 5-HT receptor (5-HTR) antagonists acting at either 5-HT1ARs or HT2Rs (Inaba et al., 2009). Even though these data suggest that 5-HT exerts a facilitating effect on LTP, there is also evidence that 5-HT can inhibit LTP induction in V1, thereby contributing to the stability of sensory networks (Edagawa et al., 1998, Edagawa et al., 2000, Gagolewicz and Dringenberg, 2016, Kim et al., 2006). The apparent discrepancy between these experimental results may be due to the differences in age and developmental status of these animals, since recent data suggest that 5-HT acts to facilitate and inhibit plasticity in juveniles and adult animals, respectively (Gagolewicz and Dringenberg, 2016).