Azobenzene/Tetraethyl Ammonium Photochromic Potassium Channel Blockers: Scope and Limitations for Design of Para-Substituted Derivatives with Specific Absorption Band Maxima and Thermal Isomerization Rate (original) (raw)
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Photochromic Potassium Channel Blockers: Design and Electrophysiological Characterization
Methods in Molecular Biology, 2013
Voltage-gated potassium ( K v ) channels are membrane proteins that open a selective pore upon membrane depolarization, allowing K + ions to fl ow down their electrochemical gradient. In neurons, K v channels play a key role in repolarizing the membrane potential during the falling phase of the action potential, often resulting in an after hyperpolarization. Opening of K v channels results in a decrease of cellular excitability, whereas closing (or pharmacological block) has the opposite effect, increased excitability. We have developed a series of photosensitive blockers for K v channels that enable reversible, optical regulation of potassium ion fl ow. Such molecules can be used for remote control of neuronal excitability using light as an on/off switch. Here we describe the design and electrophysiological characterization of photochromic blockers of ion channels. Our focus is on K v channels but in principle, the techniques described here can be applied to other ion channels and signaling proteins.
European Journal of Medicinal Chemistry, 2020
By linking two N-methyl-N-carbocyclic quaternary ammonium groups to an azobenzene scaffold in meta-or para-positions we generated a series of photoswitchable neuromuscular ligands for which we coined the term "azocuroniums". These compounds switched between the (E)-and (Z)-isomers by light irradiation at 400-450 nm and 335-340 nm, respectively. Meta-azocuroniums were potent nicotinic ligands with a clear selectivity for the muscular nAChRs compared to neuronal α7 and α4β2 subtypes, showed good solubility in physiologic media, negligible cell toxicity, and would not reach the CNS. Electrophysiological studies in muscle-type nAChRs expressed in Xenopus laevis oocytes showed that (E)-isomers were more potent than (Z)-forms. All meta-azocuroniums were neuromuscular blockers, with the exception of the pyrrolidine derivative that was an agonist. These new meta-azocuroniums, which can be modulated ad libitum by light, could be employed as photoswitchable muscle relaxants with fewer side effects for surgical interventions and as tools to better understand the pharmacology of muscle-type nAChRs.
A photoswitchable GABA receptor channel blocker
British Journal of Pharmacology, 2019
Background and PurposeAnion‐selective Cys‐loop receptors (GABA and glycine receptors) provide the main inhibitory drive in the CNS. Both types of receptor operate via chloride‐selective ion channels, though with different kinetics, pharmacological profiles, and localization. Disequilibrium in their function leads to a variety of disorders, which are often treated with allosteric modulators. The few available GABA and glycine receptor channel blockers effectively suppress inhibitory currents in neurons, but their systemic administration is highly toxic. With the aim of developing an efficient light‐controllable modulator of GABA receptors, we constructed azobenzene‐nitrazepam (Azo‐NZ1), which is composed of a nitrazepam moiety merged to an azobenzene photoisomerizable group.Experimental ApproachThe experiments were carried out on cultured cells expressing Cys‐loop receptors of known subunit composition and in brain slices using patch‐clamp. Site‐directed mutagenesis and molecular mod...