Relationship between brain levels of 3-(3-hydroxyphenyl)-N-n- propylpiperidine HCl enantiomers and effects on locomotor activity in rats

J Lundstrom, JE Lindgren, S Ahlenius and V Hillegaart

Department of Drug Metabolism, Astra Research Centre AB, Sodertalje, Sweden.

After s.c. administration of 3-(3-hydroxyphenyl)-N-n-propylpiperidine HCl (3-PPP) to rats, plasma and brain levels were monitored in relation to the amount of spontaneous locomotor activity. Based on time-course relationships, concentration-effect curves were elaborated after administration of (-)3-PPP and (+)3-PPP in the dose range of 1 to 256 mumol.kg-1. Both enantiomers were readily absorbed and distributed, as evidenced by a close correlation between brain and plasma levels, brain levels being 7 to 9 times higher than those found in plasma. Plasma half-lives were 25 and 32 min for (-)3-PPP and (+)3-PPP, respectively. Plotting brain concentrations of (-)3-PPP against locomotor activity resulted in a good fit to a declining two-phase curve, in all probability reflecting preferential actions at pre- and postsynaptic dopamine receptors, respectively. These two underlying mechanisms could also be identified from the biphasic effects produced by (+)3-PPP on locomotor activity: suppression followed by stimulation, respectively. Together, these observations provide further support for the contention that at low doses, both enantiomers have sedative actions due to stimulation of inhibitory autoreceptors. With increasing doses, however, a postsynaptic receptor blockade will predominate for a partial agonist like (-)3-PPP, producing suppression of locomotion, whereas the full agonist, (+)3-PPP, will produce behavioral activation due to stimulation of postsynaptic receptors.

Volume 262, Issue 1, pp. 41-47, 07/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics