(+ 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 a mphetamine derivative 1-(2,5-dimethoxy-4-ethylthiophenyl)-2-aminopropa ne (ALEPH-2), were examined in rodents in order to elucidate the mecha nism underlying its anxiolytic-like effect. After peripheral administr ation in rats, ALEPH-2 induced some symptoms of the serotonergic syndr ome, e.g. forepaw treading and flat body posture. Additionally, a decr ease in motor activity was observed. No significant effects on the num ber of head shakes were observed after injection, although high inter- subject variability was noted. Higher doses of ALEPH-2, in the range e xhibiting anxiolytic properties (4 mg/kg), elicited significant hypoth ermia in mice. The affinity of the drug for 5-HT2A/2C receptors ([H-3] ketanserin sites) was in the nanomolar range (K-i = 173 nM), whereas f or 5-HT1A, benzodiazepine sites, and GABA(A) receptors, the affinity w as micromolar or lower. Based on these results the mechanism of action and the anxiolytic-like properties of ALEPH-2 are discussed.