Evaluation of the eutomer of 4-{3-(4-chlorophenyl)-3-hydroxypyrrolidin-1-yl}-1-(4-fluorophenyl)butan-1-one, {(+)-SYA 09}, a pyrrolidine analog of haloperidol

Enantionteric separation of the racemic 4-{3-(4-chlorophenyl)-3-hydroxypyrrolidin-1-yl}-1-(4-fluorophenyl)butan-1-one, a pyrrolidine analog of haloperidol, {(+/-)-SYA 09}, and subsequent binding studies revealed that most of the binding affinity at dopamine and serotonin receptors resides in the (+)-isomer {(+)-SYA 09} or the eutomer. Further pharmacological evaluation of the eutomer revealed that it has a higher affinity for the dopamine D4 (DAD4) receptor subtype (K-i = 3.6 nM) than for the DAD2 subtype (K-i = 51.1 nM) with a ratio of 14.2 (D2K(i)/D4K(i) ratio = 14.2). In an animal model of antipsychotic efficacy, the (+)-SYA 09 was efficacious with an ED50 value of 1.6 mg/kg, ip, and at twice this value, (+)-SYA 09 did not induce significant catalepsy in rats. (c) 2006 Elsevier Ltd. All rights reserved.