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-diisopropylphenol (propofol) have been recently synthesised with the aim of exploring the structure-activity relationships. 2. In the present study, the effects of one such compound, 4-iodo-2,6-diisopropylphenol (4-I-Pro), on gamma-aminobutyric acid type A (GABA(A)) receptors 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-clamp recording. 3. 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 alpha1beta2gamma2S receptors was markedly less than that of propofol. 4. Similarly to propofol, 4-I-Pro potentiated in a concentration-dependent manner GABA-evoked Cl- currents measured at different GABA(A) receptor constructs. 5. 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. 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 reduced acetylcholine release in the hippocampus of freely moving rats. 8. 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.
Sanna
E
E
Department of Experimental Biology, University of Cagliari, Cittadella Universitaria Monserrato (CA), Italy. esanna@vaxcal.unica.it
Motzo
C
C
Usala
M
M
Serra
M
M
Dazzi
L
L
Maciocco
E
E
Trapani
G
G
Latrofa
A
A
Liso
G
G
Biggio
G
G
D000109:Acetylcholine / Q000378:metabolism; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology; D018118:Chloride Channels / Q000187:drug effects; D003220:Conflict, Psychological; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009865:Oocytes; D015742:Propofol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy; D014981:Xenopus; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
C112421:4-iodo-2,6-diisopropylphenol; D000777:Anesthetics; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D018118:Chloride Channels; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D000109:Acetylcholine; D015742:Propofol