Differential stereoselectivity of methotrimeprazine enantiomers for selected central nervous system receptor types

TA Robert, AN Hagardorn and EA Daigneault

Optical isomers of methotrimeprazine, an analgesic/neuroleptic, were investigated with respect to their ability to interact with six receptor types or subtypes. Bovine caudate nucleus tissue homogenates provided the dopamine, opiate, and serotonin receptor populations studied in these experiments. The radioligands used in saturation and binding competition experiments were tritiated dopamine, spiperone, dihydromorphine, 5-L-methionine enkephalin, naloxone, and 5- hydroxytryptamine. Saturation experiments verified acceptable performance of these in vitro receptor assay systems and indicated that a one-site binding model was adequate for each of these ligands under the experimental conditions employed. The competition experiments exhibited statistically significant (p less than 0.05) differences in isomeric effects only for dopamine and 5-hydroxytryptamine receptors. The more active isomer, levorotatory methotrimeprazine, was shown to be pharmacodynamically equivalent to chlorpromazine at these receptor types. When the magnitude of receptor stereoselectivity is plotted against an estimate of the more active isomer's affinity for that particular receptor, an excellent correlation is observed. This suggests that a high degree of stereoselectivity characterizes a highly specific drug/receptor interaction. These findings are compatible with the conclusion that methotrimeprazine does not produce analgesia via a direct action upon opiate receptors.

Volume 21, Issue 2, pp. 315-319, 03/01/1982
Copyright © 1982 by American Society for Pharmacology and Experimental Therapeutics