Characterization of the electrophysiological and pharmacological effects of 4-iodo-2,6-diisopropylphenol, a propofol analogue devoid of sedative-anaesthetic properties

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Abstract
Several derivatives and analogues of the general anaesthetic 2,6‐diisopropylphenol (propofol) have been recently synthesised with the aim of exploring the structure‐activity relationships. In the present study, the effects of one such compound, 4‐iodo‐2,6‐diisopropylphenol (4‐I‐Pro), on γ‐aminobutyric acid type A (GABAA) receptors in vitro were compared with its in vivo effects in rodents. Human GABAA receptors were expressed in Xenopus oocytes, and the actions of 4‐I‐Pro on receptor function were compared with those of propofol by two‐electrode voltage‐clamp recording. Similar to propofol, 4‐I‐Pro directly activated Cl− currents in the absence of GABA at all combinations of receptor subunits tested. However, the efficacy of 4‐I‐Pro in inducing direct activation of α1β2γ2S receptors was markedly less than that of propofol. Similarly to propofol, 4‐I‐Pro potentiated in a concentration‐dependent manner GABA‐evoked Cl− currents measured at different GABAA receptor constructs. As expected, intraperitoneal injection of propofol induced sedation, ataxia, and loss of the righting reflex in rats. In contrast, administration of 4‐I‐Pro failed to produce any of these behavioural effects. Administration of 4‐I‐Pro to rats reduced in a dose‐dependent manner the incidence of tonic‐clonic seizures induced by pentylenetetrazol and induced an anticonflict effect as measured in the Vogel test. Microdialysis revealed that, like propofol, administration of 4‐I‐Pro reduced acetylcholine release in the hippocampus of freely moving rats. These results demonstrate that para‐substitution of the phenol ring of propofol with iodine yields a compound that exhibits anticonvulsant and anticonflict effects, but is devoid of sedative‐hypnotic and anaesthetic properties. Thus, 4‐I‐Pro possesses pharmacological characteristics more similar to anxiolytic and anticonvulsant drugs than to general anaesthetics. British Journal of Pharmacology (1999) 126, 1444–1454; doi:10.1038/sj.bjp.0702449