(+/-)-1-(2,5-Dimethoxy-4-ethylthiophenyl)-2-aminopropane (ALEPH-2), a novel putative anxiolytic agent lacking affinity for benzodiazepine sites and serotonin-1A receptors.
Serotonergic behavioral responses, effects on motor activity and core temperature, and binding properties of the novel putative anxiolytic amphetamine derivative (+/-)1-(2,5-dimethoxy-4-ethylthio-phenyl)-2-aminopropane (ALEPH-2), were examined in rodents in order to elucidate the mechanism underlying its anxiolytic-like effect. After peripheral administration in rats, ALEPH-2 induced some symptoms of the serotonergic syndrome, e.g. forepaw treading and flat body posture. Additionally, a decrease in motor activity was observed. No significant effects on the number of head shakes were observed after injection, although high inter-subject variability was noted. Higher doses of ALEPH-2, in the range exhibiting anxiolytic properties (4mg/kg), elicited significant hypothermia in mice. The affinity of the drug for 5-HT2A/2C receptors ([3H]ketanserin sites) was in the nanomolar range (Ki = 173 nM), whereas for 5-HT1A, benzodiazepine sites, and GABAA receptors, the affinity was micromolar of lower. Based on these results the mechanism of action and the anxiolytic-like properties of ALEPH-2 are discussed.
Reyes-Parada
M
M
Cell Biology Division, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay.
Scorza
C
C
Romero
V
V
Silveira
R
R
Medina
J H
JH
Andrus
D
D
Nichols
D E
DE
Cassels
B K
BK
D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001665:Binding Sites; D001831:Body Temperature / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007035:Hypothermia / Q000139:chemically induced; D007650:Ketanserin / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism / Q000502:physiology; D011985:Receptors, Serotonin / Q000378:metabolism / Q000502:physiology; D012702:Serotonin Antagonists / Q000378:metabolism
D014151:Anti-Anxiety Agents; D011963:Receptors, GABA-A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine; D007650:Ketanserin; C103735:1-(2,5-dimethoxy-4-ethylthiophenyl)-2-aminopropane