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

1 Several derivatives and analogues-of the-general anaesthetic 2,6-diisopro pylphenol (propofol) have been recently synthesised with the aim of explori ng the structure-activity relationships. 2 In the present study, the effects of one such compound, 4-iodo-2,6-diisop ropylphenol (4-I-Pro), on gamma-aminobutyric acid type A (GABA(A)) receptor s in vitro were compared with its in vivo effects in rodents.- Human GABA(A ) 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-cramp recording. 3 Similar to propofol, 4-I-Pro directly activated Cl- currents in the absen ce of GABA at all combinations of receptor subunits tested. However, the ef ficacy of 4-I-Pro in inducing direct activation of alpha 1 beta 2 gamma 2S receptors was markedly less than that of propofol. 4 Similarly to propofol, 4-I-Pro potentiated in a concentration-dependent m anner GABA-evoked Cl- currents measured at different GABA(A) receptor const ructs. 5 As expected, intraperitoneal injection of propofol induced sedation, atax ia, and loss of the righting reflex in rats. In contrast, administration of 4-I-Pro failed to produce any of these behavioural effects. 6 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. 7 Microdialysis revealed that, like propofol, administration of 4-I-Pro red uced acetylcholine release in the hippocampus of freely moving rats. 8 These results demonstrate that pare-substitution of the phenol ring of pr opofol with iodine yields a compound that exhibits anticonvulsant and antic onflict effects, but is devoid of sedative-hypnotic and anaesthetic propert ies. Thus, 4-I-Pro possesses pharmacological characteristics more similar t o anxiolytic and anticonvulsant drugs than to general anaesthetics.