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Dopamine D-2 agonists with high and low efficacies: differentiation by behavioural techniques

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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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  1. J. Arnt

    Present address: Pharmacological Research, H. Lundbeck A/S, Copenhagen, Denmark

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  1. Pharmacological Research, H. Lundbeck A/S, Copenhagen, Denmark

    J. Hyttel

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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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