Summary
The effects of the dopamine (DA) D-2 antagonist YM 09151-2 and the DA D-2 agonists terguride, preclamol, EMD 23448, B-HT 920, quinpirole and (−)-NPA were studied in a battery of behavioural tests in order to evaluate their relative efficacies. Furthermore, their affinities for DA D-2 receptors labelled by3H-N-0437 were measured in vitro. All agonists reduced spontaneous locomotor activity and induced marked contralateral circling behaviour in 6-hydroxy-DA-lesioned rats. Quinpirole and (−)-NPA increased motor activity after high doses. YM 09151-2 did not induce circling. In hemitransected rats quinpirole and (−)-NPA had weak effects when given alone, whereas the other agonists were ineffective. After combination with DA D-1 agonist SK&F 38393, B-HT 920 became effective, and the effects of quinpirole and (−)-NPA were facilitated. EMD 23448, preclamol and terguride were not active. In contrast, the two latter compounds fully inhibited the response to apomorphine. In stereotypy experiments a similar activity pattern was observed. Finally, drug discrimination studies showed that quinpirole, (−)-NPA and B-HT 920 substituted for the stimulus effects induced by d-amphetamine or (−)-NPA in different groups of rats. EMD 23448 induced intermediate effects, whereas preclamol and terguride had weak effects. None of the partial agonists inhibited the response of d-amphetamine. YM 09151-2 potently inhibited the effect of d-amphetamine.
The results suggest that DA D-2 agonists can be ranked according to gradually increasing agonist efficacies rather than classified into autoreceptorselective versus nonselective D-2 agonists. Implications of this hypothesis are discussed.
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Abbreviations
- YM 09151-2 :
-
([N-(2RS,3RS)-1-benzyl-2-methyl-3-pyrrolidinyl]-5-chloro-2-methoxy-4-methylaminobenzamide)
- 3-PPP :
-
(3-(3-hydroxyphenyl)-N-n-propylpiperidine). Preclamol is the INN name of the (−)-enantiomer
- EMD 23448 :
-
(3-(4-(4-phenyl-1,2,3,6-tetrahydropyridyl-(1))-butyl)-indole)
- B-HT 920 :
-
(6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d]azepine)
- (−)-NPA :
-
((−)-N-n-propylnorapomorphine)
- SK&F 38393 :
-
(2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine)
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Arnt, J., Hyttel, J. Dopamine D-2 agonists with high and low efficacies: differentiation by behavioural techniques. J. Neural Transmission 80, 33–50 (1990). https://doi.org/10.1007/BF01245021
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DOI: https://doi.org/10.1007/BF01245021