Abstract

Previous studies with (S)-(+)-N-n-propylnorapomorphine (NPA), an enantiomer of the potent dopaminergic agonist (R)-(-)-NPA, showed that this compound had a complex pharmacological profile. For example, (S)-(+)NPA had weak dopaminergic agonist potency, in that it could slow and ultimately stop firing of substantia nigra and ventral tegmental area dopamine neurons. However, antagonist properties were also evident inasmuch as immediate pretreatment with a low dose of (S)-(+)-NPA caused a significant rightward shift of the (R)-(-)-NPA dose-response curve. This dual agonist-antagonist nature of (S)-(+)-NPA suggested a low intrinsic efficacy for (S)-(+)-NPA. To test this hypothesis, we conducted dose-response studies for the inhibition of rat substantia nigra dopamine cell firing by (R)-(-)- and (S)-(+)-NPA 1 day after partial irreversible dopamine receptor inactivation with 6 mg/kg N-ethoxycarbonyl-2-ethoxy-1-2-dihydroquinoline (EEDQ) in an ethanol vehicle. This degree of inactivation resulted in a significant, parallel, rightward shift of the (R)-(-)-NPA dose-response curve relative to ethanol-treated control rats, with no loss of maximal response. After pretreatment with the same dose of EEDQ, however, the maximal response to (S)-(+)-NPA was reduced by 22% with no shift on the dose axis. The dose-response curves for control and EEDQ-treated groups were subjected to Furchgott analysis to determine per cent response versus fractional occupancy relationships for each drug. A steep hyperbolic relationship was revealed for (R)-(-)-NPA. Fifty per cent and maximal (greater than 95%) inhibitions of cell firing occurred at 3.5% and approximately 32% receptor occupancies, respectively. Hence, for (R)-(-)-NPA there is about a 68% receptor reserve in this model. The same analysis for (S)-(+)-NPA yielded an occupancy versus response plot that was more shallow and linear. Half-maximal effects occurred at 66% occupancy and the maximal response (96% inhibition) required 94% occupancy, indicating few spare receptors for (S)-(+)-NPA. Because the ratio of fractional occupancies at a given level of response is a measure of relative efficacy, we calculated a relative efficacy of (S)-(+)- to (R)-(-)-NPA of 0.05 (at the 50% response level). This confirms that (S)-(+)-NPA indeed has a much lower intrinsic efficacy than the (R)-(-)-antipode and may account for the previously reported antagonist property of the (+)-form under certain treatment conditions.