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Anion Recognition by a Pincer-Type Host Constructed from Two Polyamide Macrocyclic Frameworks Jointed by a Photo-Addressable Azobenzene Switch.

ABSTRACT: A sterically crowded light-responsive host 1 was synthetized with a 93% yield by applying a post-functionalization protocol utilizing the double amidation of 4,4'-azodibenzoyl dichloride with a readily available 26-membered macrocyclic amine. X-ray structures of two hydrates of trans-1 demonstrate a very different alignment of the azobenzene linkage, which is involved in T-shape or parallel-displaced π⋯π stacking interactions with the pyridine-2,6-dicarboxamide moieties from the macrocyclic backbone. Despite the rigidity of the macrocyclic framework, which generates a large steric hindrance around the azobenzene chromophore, the host 1 retains the ability to undergo a reversible cis⟷trans isomerization upon irradiation with UVA (368 nm) and blue (410 nm) light. Moreover, thermal cis→trans back-isomerization (ΔG⁰ = 106.5 kJ∙mol^-1, t_½ = 141 h) is markedly slowed down as compared to the non-macrocyclic analog. ¹H NMR titration experiments in DMSO-d₆/0.5% water solution reveal that trans-1 exhibits a strong preference for dihydrogenphosphate (H₂PO₄^-) over other anions (Cl^-, MeCO₂^-, and PhCO₂^-), whereas the photogenerated metastable cis-1 shows lower affinity for the H₂PO₄^- anion.

SUBMITTER: Niedbala P

PROVIDER: S-EPMC8777895 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND AND PURPOSE:The photo-isomerizable local anaesthetic, quaternary ammonium-azobenzene-quaternary ammonium (QAQ), provides rapid, optical control over pain signalling without involving genetic modification. In darkness or in green light, trans-QAQ blocks voltage-gated K+ and Na+ channels and silences action potentials in pain-sensing neurons. Upon photo-isomerization to cis with near UV light, QAQ blockade is rapidly relieved, restoring neuronal activity. However, the molecular mechanism of cis and trans QAQ blockade is not known. Moreover, the absorption spectrum of QAQ requires UV light for photo-control, precluding use deep inside neural tissue. EXPERIMENTAL APPROACH:Electrophysiology and molecular modelling were used to characterize the binding of cis and trans QAQ to voltage-gated K+ channels and to develop quaternary ammonium-ethylamine-azobenzene-quaternary ammonium (QENAQ), a red-shifted QAQ derivative controlled with visible light. KEY RESULTS:trans QAQ was sixfold more potent than cis QAQ, in blocking current through Shaker K+ channels. Both isomers were use-dependent, open channel blockers, binding from the cytoplasmic side, but only trans QAQ block was slightly voltage dependent. QENAQ also blocked native K+ and Na+ channels preferentially in the trans state. QENAQ was photo-isomerized to cis with blue light and spontaneously reverted to trans within seconds in darkness, enabling rapid photo-control of action potentials in sensory neurons. CONCLUSIONS AND IMPLICATIONS:Light-switchable local anaesthetics provide a means to non-invasively photo-control pain signalling with high selectivity and fast kinetics. Understanding the mode of action of QAQ and related compounds will help to design of drugs with improved photo-pharmacological properties. LINKED ARTICLES:This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

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Anion Recognition by a Pincer-Type Host Constructed from Two Polyamide Macrocyclic Frameworks Jointed by a Photo-Addressable Azobenzene Switch.

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