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Azi-medetomidine: Synthesis and Characterization of a Novel ?2 Adrenergic Photoaffinity Ligand.

ABSTRACT: Agonists at the ?2 adrenergic receptor produce sedation, increase focus, provide analgesia, and induce centrally mediated hypotension and bradycardia, yet neither their dynamic interactions with adrenergic receptors nor their modulation of neuronal circuit activity is completely understood. Photoaffinity ligands of ?2 adrenergic agonists have the potential both to capture discrete moments of ligand-receptor interactions and to prolong naturalistic drug effects in discrete regions of tissue in vivo. We present here the synthesis and characterization of a novel ?2 adrenergic agonist photolabel based on the imidazole medetomidine called azi-medetomidine. Azi-medetomidine shares protein association characteristics with its parent compound in experimental model systems and by molecular dynamics simulation of interactions with the ?2A adrenergic receptor. Azi-medetomidine acts as an agonist at ?2A adrenergic receptors, and produces hypnosis in Xenopus laevis tadpoles. Azi-medetomidine competes with the ?2 agonist clonidine at ?2A adrenergic receptors, which is potentiated by photolabeling, and azi-medetomidine labels moieties on the ?2A adrenergic receptor as determined by mass spectrometry in a manner consistent with a simulated model. This novel ?2 adrenergic agonist photolabel can serve as a powerful tool for in vitro and in vivo investigations of adrenergic signaling.

SUBMITTER: McKinstry-Wu AR

PROVIDER: S-EPMC6889220 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Azi-medetomidine: Synthesis and Characterization of a Novel α2 Adrenergic Photoaffinity Ligand.

McKinstry-Wu Andrew R AR Woll Kellie A KA Joseph Thomas T TT Bu Weiming W White E Railey ER Bhanu Natarajan V NV Garcia Benjamin A BA Brannigan Grace G Dailey William P WP Eckenhoff Roderic G RG

ACS chemical neuroscience 20191105 11

Agonists at the α<sub>2</sub> adrenergic receptor produce sedation, increase focus, provide analgesia, and induce centrally mediated hypotension and bradycardia, yet neither their dynamic interactions with adrenergic receptors nor their modulation of neuronal circuit activity is completely understood. Photoaffinity ligands of α<sub>2</sub> adrenergic agonists have the potential both to capture discrete moments of ligand-receptor interactions and to prolong naturalistic drug effects in discrete r ...[more]

PMID: 31638765

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Project description:The amyloid beta (Aβ) pathway is strongly implicated in neurodegenerative conditions such as Alzheimer's disease and more recently, glaucoma. Here, we identify the α2 adrenergic receptor agonists (α2ARA) used to lower intraocular pressure can prevent retinal ganglion cell (RGC) death via the non-amyloidogenic Aβ-pathway. Neuroprotective effects were confirmed in vivo and in vitro in different glaucoma-related models using α2ARAs brimonidine (BMD), clonidine (Clo) and dexmedetomidine. α2ARA treatment significantly reduced RGC apoptosis in experimental-glaucoma models by 97.7% and 92.8% (BMD, P<0.01) and 98% and 92.3% (Clo, P<0.01)) at 3 and 8 weeks, respectively. A reduction was seen in an experimental Aβ-induced neurotoxicity model (67% BMD and 88.6% Clo, both P<0.01, respectively), and in vitro, where α2ARAs significantly (P<0.05) prevented cell death, under both hypoxic (CoCl2) and stress (UV) conditions. In experimental-glaucoma, BMD induced ninefold and 25-fold and 36-fold and fourfold reductions in Aβ and amyloid precursor protein (APP) levels at 3 and 8 weeks, respectively, in the RGC layer, with similar results with Clo, and in vitro with all three α2ARAs. BMD significantly increased soluble APPα (sAPPα) levels at 3 and 8 weeks (2.1 and 1.6-fold) in vivo and in vitro with the CoCl2 and UV-light insults. Furthermore, treatment of UV-insulted cells with an sAPPα antibody significantly reduced cell viability compared with BMD-treated control (52%), co-treatment (33%) and untreated control (27%). Finally, we show that α2ARAs modulate levels of laminin and MMP-9 in RGCs, potentially linked to changes in Aβ through APP processing. Together, these results provide new evidence that α2ARAs are neuroprotective through their effects on the Aβ pathway and sAPPα, which to our knowledge, is the first description. Studies have identified the need for α-secretase activators and sAPPα-mimetics in neurodegeneration; α2ARAs, already clinically available, present a promising therapy, with applications not only to reducing RGC death in glaucoma but also other neurodegenerative processes involving Aβ.

Project description:Background:Moringa peregrina (M. peregrina) is an edible, drought-resistant tree that is native to semi-arid countries. It is used as a painkiller in folk medicine. Aims:To study the antinociceptive effects of the leaf extract of M. peregrina in mice. Study Design:Animal experimentation. Methods:We employed thermal (hot plate and tail-immersion tests) and chemical (writhing and formalin tests) pain models in male BALB/c mice (eight animals per group) to investigate the mechanisms involved in the antinociceptive actions of M. peregrina. Additionally, we identified the chemical constituents present in the extract of M. peregrina by using liquid chromatography-mass spectrometry analysis, and predicted the possible active constituents that interact with the receptor based on molecular docking simulations. Results:In the writhing test, 200 mg/kg of M. peregrina extract restricted abdominal cramps by up to 55.97% (p<0.001). Further, it reduced the time of paw-licking in the early and late phases of formalin test by up to 56.8% and 65.5%, respectively, as compared to the percentage inhibitions of 50.5% and 48.4% produced by 30 mg/kg diclofenac sodium in the early and late phases, respectively (p<0.05). This effect was abrogated by yohimbine (1 mg/kg, intraperitoneally), but not by methysergide (5 mg/kg, intraperitoneally), in the late phase only, which indicates that the action of M. peregrina in formalin test is not mediated by 5-HT2 serotonin receptors, but rather via α2-adrenergic receptors. In the hot plate test, but not on tail-immersion test, the high dose (400 mg/kg) of the extract increased the latency time after 30 minutes of its administration. Yohimbine antagonized the action of M. peregrina in the hot plate test. Based on LC-MS analysis, the major constituents found in M. peregrina methanolic extract were chrysoeriol 7-O-diglucoside, lupeol acetate, quercetin, and rutin. Depending on the molecular docking results, the activity of M. peregrina extract could be due to the binding of chrysoeriol 7-O-diglucoside, quercetin, and rutin to the α2-adrenergic receptor. Conclusion:Interaction with the α2-adrenergic receptor serves as a possible mechanism of the M. peregrina analgesic effect.

Dataset Information

Azi-medetomidine: Synthesis and Characterization of a Novel ?2 Adrenergic Photoaffinity Ligand.

Publications

Azi-medetomidine: Synthesis and Characterization of a Novel α2 Adrenergic Photoaffinity Ligand.

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