Behavioral effects of the R-(+)- and S-(-)-enantiomers of the dopamine D(1)-like partial receptor agonist SKF 83959 in monkeys

Abstract

Dopamine D(1)-like partial receptor agonists such as SKF 83959 have been proposed as potential candidates for the treatment of cocaine addiction. The present studies were conducted to further characterize SKF 83959 by pharmacologically evaluating effects of its R-(+)- and S-(-)-enantiomers, MCL 202 and MCL 201, respectively, on overt behavior (eye blinking) and schedule-controlled performance in squirrel monkeys. MCL 202, like the D(1) full receptor agonist SKF 82958, produced dose-related increases in eye blinking and decreases in rates of fixed-ratio responding. However, the magnitude of effects of MCL 202 on eye blinking was less than observed with SKF 82958. In contrast to the effects of its R-(+) enantiomer, MCL 201 was relatively devoid of behavioral activity up to doses that were approximately 10-fold greater than MCL 202. Pretreatment with the selective D(1)-like receptor antagonist SCH 39166 dose-dependently antagonized increases in eye blinking produced by MCL 202, confirming the involvement of D(1) mechanisms in its effects. A dose-ratio analysis of the antagonism of effects of MCL 202 by SCH 39166 revealed an apparent pA(2) value of 7.675 with a slope of -0.78+/-0.04. In further studies, pretreatment with MCL 202 antagonized the effects of SKF 82958 on eye blinking and, like SCH 39166, schedule-controlled behavior in a dose-related manner. A dose-ratio analysis of the antagonist effects of MCL 202 on the SKF 82958-induced increases in eye blinking revealed ratios of 2.7, 4.8 and 31.1 for 0.1, 0.3 and 1.0 mg/kg dose of the antagonist, respectively, indicative of a significant change in the potency of SKF 82958. These results suggest that MCL 202, like its parent compound SKF 83959, has both D(1) receptor-mediated agonist and antagonist properties, consistent with its characterization as a partial agonist at the D(1)-like receptor. In addition, the inactivity of MCL 201, the S-(-)-enantiomer, suggests that the behavioral effects of SKF 83959 can be attributed primarily to the activity of its R-(+)-enantiomer.

Fig. 1

Chemical structures of dopamine D₁-like receptor-selective phenyl-benzazepines.

Fig. 2

The effects of dopamine D₁-like receptor agonists, SKF 82958, MCL 201, and MCL 202 on eye blinking in squirrel monkeys. Ordinates, eye blink rates as a percentage of that obtained after vehicle injections. Abscissa, cumulative dose of drugs in mg/kg. Each point represents the average effect determined in all four monkeys. Results are presented as mean % control (+ S.E.M). Note that the R[+] enantiomer of SKF 83959, MCL 202 significantly increased rates of eye blinking, whereas the S[−] enantiomer of SKF 83959, MCL 201 failed to induced eye blinking in squirrel monkeys, and that both these compounds were less effective than SKF 82958. For all drugs, when apparently absent, error bars are within the symbol. * indicates significantly different from vehicle group (Dunnetts t-test, P < 0.05, on means derived from main effect of dose).

Fig. 3

Changes in the MCL 202 dose-effect curve for rates of eye blinking produced by pretreatments with several doses of the dopamine D₁-like receptor antagonist SCH 39166. Ordinates, eye blink rates as a percentage of that obtained after vehicle injections. Abscissa, cumulative dose of MCL 202 in mg/kg. Data are presented at as mean % control (+ S.E.M) of n = 4 animals. Schild plot analysis of the results reveals a slope of -0.96 (± 0.08) and a pA₂ value of 8.01. Note that pretreatment with SCH 39166 produced a dose-related rightward shift in the MCL 202-induced dose-effect curve.

Fig. 4

Changes in the SKF 82958 dose-effect curve for rates of eye blinking produced by pretreatments with several doses of the R[+] enantiomer of SKF 83959, MCL 202. Ordinates, eye blink rates as a percentage of that obtained after vehicle injections. Abscissa, cumulative dose of SKF 82958 in mg/kg. Schild plot analysis of the data shows a slope of −0.79 (± 0.11) and a pA₂ value of 7.07. Note that pretreatment with MCL 202 produced a dose-related rightward shift in the SKF 82958-induced dose-effect curve. Other details as in Fig. 2.

Fig. 5

The effects of dopamine D₁-like receptor agonists, SKF 82958, MCL 201, and MCL 202 on scheduled controlled behavior. Ordinates, response rates expressed as a percentage of that obtained after vehicle injections. Abscissa, cumulative dose of drugs in mg/kg. Each point represents the average effect determined in three to four monkeys. Results are presented as mean % control (+ S.E.M). Note that the R[+] enantiomer of SKF 83959, MCL 202 significantly decreased response rates, whereas the S[−] enantiomer of SKF 83959, MCL 201 failed to alter rates of responding in squirrel monkeys, and that both these compounds were less effective than SKF 82958. * indicates significantly different from vehicle group (Dunnetts t-test, P < 0.05, on means derived from main effect of dose).

Fig. 6

Changes in the SKF 82958 dose-effect curve for response rates of stimulus shock control produced by pretreatments with several doses of the dopamine D₁-like receptor antagonist SCH 39166. Ordinates, response rates expressed as a percentage of that obtained after vehicle injections. Abscissa, cumulative dose of SKF 82958 in mg/kg. Other details as in Fig. 4. Note that pretreatment with SCH 39166 produced a dose-related rightward shift in the SKF 82958-induced dose-effect curve.

Fig. 7

Changes in the SKF 82958 dose-effect curve for response rates of stimulus shock control produced by pretreatments with several doses of the R[+] enantiomer of SKF 83959, MCL 202. Ordinates, response rates expressed as a percentage of that obtained after vehicle injections. Abscissa, cumulative dose of SKF 82958 in mg/kg. Other details as in Fig. 4. Note that pretreatment with MCL 202 produced a dose-related rightward shift in the SKF 82958-induced dose-effect curve.