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Common marmosets show parkinsonian motor deficits following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration and develop dyskinesias during chronic L-dopa exposure. The D1 agonists A-77636 [(1R, 3S) 3-(1'-adamantyl)-1-aminomethyl-3, 4-dihydro-5, 6-dihydroxy-1H-2-benzopyran HCl] and A-86929 [(-)-trans 9, 10-hydroxy-2-propyl-4, 5, 5a, 6, 7, 11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride] possess potent antiparkinsonian activity in the MPTP-treated marmoset and we now assess their influence on L-dopa-induced dyskinesias. MPTP-treated marmosets with stable motor deficits were treated with L-dopa plus carbidopa for 28 days to induce dyskinesias. Subsequently, they received A-86929 for 10 days, initially at 0.5 micromol/kg and then at 1.0 micromol/kg for a further 5 days. Several months later, L-dopa 12.5 mg/kg plus carbidopa 12.5 mg/kg was given orally twice daily for 7 days, followed by A-77636 1 micromol/kg for 10 days, and then both A-77636 and L-dopa plus carbidopa were given concurrently for 3 further days. In these L-dopa-primed animals, A-86929 effectively reversed akinesia and produced dose-dependent dyskinesias which were significantly less intense than those produced by L-dopa administration. A degree of behavioral tolerance was encountered, but antiparkinsonian activity was preserved and elicited behaviour was free of hyperkinesis and stereotypy and more naturalistic than that seen with L-dopa. After a week of twice-daily L-dopa dosing, administration of the long-acting D1 agonist A-77636 initially dramatically enhanced locomotion and reproduced dyskinesia with prominent dystonia, but after repeated administration of A-77636, dyskinesia and in particular chorea, gradually disappeared. Tolerance to locomotor stimulation greater than with A-86929 occurred, although activity remained significantly above baseline levels. There was a marked reduction in L-dopa-induced climbing, stereotypy and hyperkinesis and behaviour more closely resembled that of normal unlesioned marmosets. Upon reintroduction of L-dopa concurrently with continued A-77636 administration, dystonic, but virtually no choreic dyskinesias appeared and behaviour was once again free of stereotypy and hyperkinesis, contrasting dramatically with the presence of these behaviours along with abundant chorea when L-dopa is given alone. These results show a lesser liability of A-86929 and A-77636 to reproduce dyskinesia in L-dopa-primed MPTP-lesioned subjects while maintaining effective antiparkinsonian activity and producing a more naturalistic motor response. The differential effects of A-77636 on chorea and dystonia, with suppression of chorea and stereotypy on co-administration with L-dopa, may reflect an altered balance of activity in the direct and indirect striatofugal pathways. These results suggest a possible role for D1 agonists in the treatment of Parkinson's disease.

The motor effects of dopamine D1 receptor activation and the optimal way to stimulate these receptors were studied in a primate model of parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), using 2 selective full dopamine D1 receptor agonists: A-77636 ([1 R,3S] 3-(1'-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1 H-2-benzopyran hydrochloride), and SKF 82958 (6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine hydrobromide). A-77636 was administered to one group of primed monkeys (N = 4) previously treated with levodopa and other dopamine receptor agonists, while SKF 82958 was given to another group of drug-naive monkeys (N = 3). These drugs have different durations of efficacy, lasting > 20 h and approximately 1 h, respectively, and were administered once daily (A-77636) or thrice daily (SKF 82958) for 7 days. Both drugs demonstrated excellent antiparkinsonian efficacy and locomotor stimulation. However, a rapid, functionally important, homologous (selective for D1 receptor agonists) desensitization process took place as early as on the second day with the longer-acting drug and a dose escalation of A-77636 failed to restore the initial benefit. Thrice daily dosing at a 4-h interval with the short-acting agent SKF 82958 maintained the maximal antiparkinsonian response but some shortening in the duration of response was observed after several days. These behavioral results show that dopamine D1 receptors are susceptible to desensitization after prolonged occupancy and can be desensitized profoundly and independently of dopamine D2 receptors in vivo in this model. Potent dopamine D1 receptor agonists with an intermediate half-life may prove to be better adjuncts in the treatment of Parkinson's disease. Clinical entities with pathologically enhanced dopamine D1 receptor-linked neural transmission might eventually also benefit from such desensitization.

A-77636 is a dopamine (DA) D1 receptor-selective agonist that was previously shown to elicit beneficial responses in animal models of Parkinson's disease (PD) (Kebabian et al.: Eur. J. Pharmacol. 229: 203, 1992). However, A-77636 is of limited potential for PD therapy because it induces rapid tolerance in vivo. To understand the basis of rapid onset of tolerance to the compound, we conducted studies to compare the in vitro properties of A-77636 and A-81686; the latter is a structurally related D1 agonist that did not induce significant tolerance in vivo under similar experimental conditions. With SK-N-MC, a neuroblastoma cell line, as an in vitro model for the D1 receptor, significant differences in D1 receptor function were noted after pretreatment with the two compounds. Specifically, 1-hr pretreatment with A-77636 resulted in significant residual cAMP production, even after the drug solution was removed and the cells were washed. The residual cAMP activity was selectively inhibited by SCH 23390, a selective D1 antagonist. The residual cAMP activity declined with pretreatment time, and after 4-hr pretreatment, little residual cAMP production was observed. Cotreatment of SK-N-MC cells with SCH 23390 and A-77636 did not prevent residual cAMP production by A-77636. In contrast, A-81686 did not elicit residual cAMP production is SK-N-MC cells. Although A-77636 treated cells were devoid of agonist response 4 hr after drug removal, A-81686-treated cells exhibited significant cAMP response after drug removal. Preincubation of rat striatal membranes with A-77636 resulted in a large decrease in D1 receptor binding, despite repeated washings, whereas A-81686 pretreatment caused only a small reduction in D1 receptor binding. On the basis of the present data, we conclude that A-77636 dissociates slowly from the D1 receptor. The continued activation of the D1 receptor by A-77636 leads to inability of the receptor to recover its responsivity, which may explain its long duration of action and its ability to induce rapid behavioral tolerance in vivo.

A-77636, ((1R,3S) 3-(1'-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benz opyran hydrochloride), is a selective dopamine D1 receptor agonist. In a battery of receptor binding assays, A-77636 shows the highest affinity (pKi = 7.40 +/- 0.09; Ki = 39.8 nM) for the dopamine D1 receptor. A-77636 is an agonist at the dopamine D1 receptors in the fish retina (pEC50 = 8.13; EC50 = 1.1 nM; intrinsic activity = 102% of dopamine) and the rat caudate-putamen (pEC50 = 8.97; intrinsic activity = 134% of dopamine). The compound is functionally inactive at dopamine D2 receptors (EC50 > 10 microM). In rats with unilateral 6-OHDA (6-hydroxydopamine) lesions of the nigro-striatal dopaminergic pathway, A-77636 elicits prolonged (> 20 h) contralateral turning that is blocked by SCH 23390, a D1 receptor antagonist, but not by haloperidol at doses selective for the dopamine D2 receptor. Higher doses of A-77636 produce forelimb clonus in rats and mice. When tested in marmosets treated with MPTP to induce a parkinsonian-like state, A-77636 increases locomotor activity and decreases the severity of the parkinsonian-like symptoms: the compound is active after either subcutaneous or oral administration. A-77641, the optical antipode of A-77636, has a lower affinity towards the dopamine D1 receptor (pKi = 5.14, Ki = 7200 nM), is less potent as a dopamine D1 receptor agonist (pEC50 = 5.65; EC50 = 2200 nM), fails to elicit turning in the 6-OHDA-lesioned rat, and lacks antiparkinsonian efficacy in the MPTP-treated marmoset.(ABSTRACT TRUNCATED AT 250 WORDS)

A68930 (5,6-dihydroxy-3-phenyl-1-aminomethyl-isochroman) is a potent (EC50 = 2.5 nmol/L) partial agonist at the D-1 dopamine receptor. In contrast, A68930 is a much weaker agonist (EC50 = 3,920 nmol/L) at the D-2 dopamine receptor. The orientation of the 3-phenyl substituent in the molecule is critical for the affinity and selectivity of the molecule towards the D-1 receptor in vitro and in vivo. The role of the D-1 receptor in the functioning of the basal ganglia is discussed.