Synthesis and Characterization of Photolabile Derivatives of Serotonin for Chemical Kinetic Investigations of the Serotonin 5-HT3 Receptor

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Abstract
A series of photolabile o-nitrobenzyl derivatives of serotonin (caged serotonin) were synthesized: the amine-linked serotonin derivatives N-(2-nitrobenzyl) serotonin (Bz-5HT) and N-(α-carboxy-2-nitrobenzyl) serotonin (N-CNB-5HT), and O-α-carboxy-2-nitrobenzyl) serotonin (O-CNB-5HT), which has the caging group attached to the phenolic OH group. All the derivatives released free serotonin when excited by 308-nm or 337-nm laser pulses. The time constant of serotonin release from N-CNB-5HT was 1.2 ms, with a quantum yield of 0.08. This is too slow for rapid chemical kinetic measurements. O-CNB-5HT is suitable for transient kinetic investigations of the serotonin 5-HT3 receptor. It released serotonin with a time constant of 16 μs and a quantum yield of 0.03. The biological properties of O-CNB-5HT were evaluated, and the applicability of the compound for kinetic studies of the 5-HT3 receptor was demonstrated. O-CNB-5HT does not activate the 5-HT3 receptor by itself, nor does it modulate the response of a cell when co-applied with serotonin. When irradiated with a 337-nm laser pulse, O-CNB-5HT released free serotonin that evoked 5-HT3 receptor-mediated whole-cell currents in NIE−115 mouse neuroblastoma cells.