Talipexole or pramipexole combinations with chloro-APB (SKF 82958) in MPTP-induced hemiparkinsonian monkeys

Abstract

The effects of two predominant dopamine D₂-like receptor agonists, talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d]-azepine dihydrochloride, B-HT 920 CL₂) and pramipexole (S(−)2-amino-4,5,6,7-tetrahydro-6-propyl-aminobenzothiazole dihydrochloride, SND 919 CL₂Y), were studied alone and in combination with the selective dopamine D₁-like receptor agonist chloro-APB ((±)6-chloro-7-8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-benzazepine hydrobromide, SKF 82958) in five chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned hemiparkinsonian Macaca nemestrina monkeys. Talipexole induced contraversive rotation in a dose-dependent manner up to 32 μg/kg, i.m. Talipexole was more potent than pramipexole (10 vs. 32 μg/kg, i.m.), but pramipexole was more efficacious in producing contraversive rotational behavior and significant hand movements in the afflicted limb. Larger doses of chloro-APB also produced contraversive rotation. Combinations of each dopamine D₂-like receptor agonist in a median effective dose with chloro-APB (23.4 and 74.8 μg/kg, i.m.) had synergistic effects, producing either addition or potentiation, depending upon the dose used. The effects noted with these combinations were less than the effect of a large dose (100 μg/kg) of pramipexole. Talipexole, in the largest dose studied (100 μg/kg, i.m.), produced sedation which was not seen with the same dose of pramipexole. No significant extrapyramidal side effects were noted with either agent.

Introduction

Two potential therapeutic agents in the treatment of Parkinson's disease have become available: talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d]-azepine dihydrochloride, B-HT 920 CL₂) and pramipexole (S(−)2-amino-4,5,6,7-tetrahydro-6-propyl-aminobenzothiazole dihydrochloride, SND 919 CL₂Y). Talipexole, which is a potent dopamine D₂-like receptor agonist both pre- and postsynaptically, as well as an α₂-adrenoceptor agonist and a weak 5-HT₃ receptor antagonist (Kobinger and Pichler, 1981; Pichler and Kobinger, 1981; Andén et al., 1982, Andén et al., 1983; Hinzen et al., 1986; Nishio et al., 1996), was effective in the treatment of Parkinson's disease in controlled clinical trials (Nakanisi et al., 1993).

Electrophysiological studies have demonstrated that talipexole acts on caudate neurons of cats and rats as a dopamine D₂-like receptor agonist (Matsubayashi et al., 1994, Matsubayashi et al., 1995; Todo et al., 1994). This drug induces yawning behavior in rats (Yamada et al., 1990) and an improvement of motor movements in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated marmosets (Irifune et al., 1993, Irifune et al., 1994). Pramipexole is primarily a dopamine D₂ receptor agonist with negligible α₂-adrenoceptor activities (Mierau and Schingnitz, 1992; Nishio et al., 1996) and 5-HT₃ receptor antagonistic properties (unpublished observations). Further studies were performed on MPTP induced hemiparkinsonian monkeys to determine the acute antiparkinsonian effects of talipexole in comparison with those of pramipexole. The role of dopamine D₁ receptors in the treatment of Parkinson's disease remains to be determined. Therefore, whether each of these agents alone or in combination with a selective dopamine D₁ receptor agonist such as chloro-APB ((±)6-chloro-7-8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-benzazepine hydrobromide, SKF 82958; Pfeiffer et al., 1982, Domino and Sheng, 1993b; Murray and Waddington, 1989; O'Boyle et al., 1989) produces an additive or potentiating effect was also examined. An additive action is defined as the two drugs together having the sum of the effects of the two drugs alone. A potentiating action is when the two drugs together have an effect greater than the sum of the effects of the two drugs alone. A synergistic action is when the two drug effects together are either additive or potentiating.