Receptor affinity, neurochemistry and behavioral characteristics of the enantiomers of thioridazine: evidence for different stereoselectivities at D1 and D2 receptors in rat brain.
The binding characteristics of the enantiomers of thioridazine were assessed in the brain of the rat using competitive radioreceptor assays with tritiated ligands selective for dopamine D1 (SCH-23390), D2 (spiperone), norepinephrine alpha-1 (prazosin) and muscarinic (quinuclinidinyl benzilate) receptors. (+)-Thioridazine was shown to have 2.7 and 4.5 times higher affinity than (-)-thioridazine for D2 and alpha-1 receptors, respectively. In contrast, (-)-thioridazine had 10 times higher affinity for the D1 receptor. Both enantiomers showed similar affinities for the muscarinic receptor. In a second experiment, thioridazine, dopamine, norepinephrine, serotonin and their metabolites were assayed in the brain of the rat after acute administration of the enantiomers of thioridazine and the assessment of catalepsy. (+)-Thioridazine was 4.1 times as potent as (-)-thioridazine in elevating the turnover of dopamine in the striatum, but neither enantiomer affected the other monoamines. The concentration of thioridazine and its metabolites in the brain, for a given dose, was similar for both enantiomers. (-)-Thioridazine induced slightly more catalepsy than (+)-thioridazine and appeared to be more toxic at large doses. While racemic thioridazine had an intermediate effect between that of its two enantiomers in the binding and neurochemical assays, it appeared to induce more catalepsy than either enantiomer, suggesting a synergistic effect in this behavioral assay. It was concluded that (+)- and (-)-thioridazine act as partially selective D2 and D1 antagonists, respectively. Therefore, clinical administration of only one enantiomer of thioridazine, rather than the currently prescribed racemate, may result in an improved therapeutic profile and so be worthy of further investigation.
Svendsen
C N
CN
Brain Tissue Resource Center, McLean Hospital, Belmont, Massachusetts 02178.
Froimowitz
M
M
Hrbek
C
C
Campbell
A
A
Kula
N
N
Baldessarini
R J
RJ
Cohen
B M
BM
Babb
S
S
Teicher
M H
MH
Bird
E D
ED
D000818:Animals; D001552:Benzazepines / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D002375:Catalepsy / Q000139:chemically induced; D018492:Dopamine Antagonists; D008297:Male; D009638:Norepinephrine; D011224:Prazosin / Q000378:metabolism; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011941:Receptors, Adrenergic / Q000187:drug effects; D011954:Receptors, Dopamine / Q000187:drug effects*; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011976:Receptors, Muscarinic / Q000187:drug effects; D013134:Spiperone / Q000378:metabolism; D013237:Stereoisomerism; D013881:Thioridazine / Q000494:pharmacology*
D001552:Benzazepines; D018492:Dopamine Antagonists; D011941:Receptors, Adrenergic; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011976:Receptors, Muscarinic; D013134:Spiperone; D011813:Quinuclidinyl Benzilate; D013881:Thioridazine; D009638:Norepinephrine; D011224:Prazosin