The pK(i) values of 13 reference typical and 7 reference atypical antipsychotic drugs (APDs) for rat striatal dopamine D-1 and D-2 receptor binding sites and cortical serotonin (5-HT2) receptor binding sites were determined. The atypical antipsychotics had significantly lower pK(i) values for the D-2 but not 5-HT2 binding sites. There was a trend for a lower pK(i) value for the D-1 binding site for the atypical APD. The 5-HT2 and D-1 pK(i) values were correlated for the typical APD whereas the 5-HT2 and D-2 pK(i) values were correlated for the atypical APD. A stepwise discriminant function analysis to determine the independent contribution of each pK(i) value for a given binding site to the classification as a typical or atypical APD entered the D-2 pK(i) value first, followed by the 5-HT2 pK(i) value. The D-1 pK(i) value was not entered. A discriminant function analysis correctly classified 19 of 20 of these compounds plus 14 of 17 additional test compounds as typical or atypical APD for an overall correct classification rate of 89.2%. The major contributors to the discriminant function were the D-2 and 5-HT2 pK(i) values. A cluster analysis based only on the 5-HT2/D2 ratio grouped 15 of 17 atypical + one typical APD in one cluster and 19 of 20 typical + two atypical APDs in a second cluster, for an overall correct classification rate of 91.9%. When the stepwise discriminant function was repeated for all 37 compounds, only the D-2 and 5-HT2 pK(i) values were entered into the discriminant function. These data suggest determination of D-2 and 5-HT2 pK(i) values may be useful for rapid screening of candidate atypical APDs with only minimal false positives. The implications of these findings for the mechanism of action of atypical APDs is discussed.
|Original language||English (US)|
|Number of pages||9|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1989|
ASJC Scopus subject areas
- Molecular Medicine