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.
Enantiomeric 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 (Ki = 3.6 nM) than for the DAD2 subtype (Ki = 51.1 nM) with a ratio of 14.2 (D2Ki/D4Ki ratio = 14.2). In an animal model of antipsychotic efficacy, the (+)-SYA 09 was efficacious with an ED50 value of 1.6 mg/kg, i.p., and at twice this value, (+)-SYA 09 did not induce significant catalepsy in rats.
Ablordeppey
Seth Y
SY
Division of Basic Pharmaceutical Sciences, Florida A& M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL 32307, USA. seth.ablordeppey@famu.edu
Lyles-Eggleston
Margaret
M
Bricker
Barbara
B
Zhang
Wang
W
Zhu
Xue
X
Goodman
Carl
C
Roth
Bryan L
BL
D000818:Animals; D002074:Butanones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003024:Clozapine / Q000737:chemistry / Q000494:pharmacology; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007536:Isomerism; D051379:Mice; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats
C512293:4-(3-(4-chlorophenyl)-3-hydroxypyrrolidin-1-yl)-1-(4-fluorophenyl)butan-1-one; D002074:Butanones; D011759:Pyrrolidines; D003024:Clozapine; D006220:Haloperidol