The results support the hypothesis that A(2A) receptor mechanisms contribute to symptom production in PD and that drugs able to selectively block these receptors may help palliate symptoms in levodopa-treated patients with this disorder.

Intermittent stimulation of striatal dopaminergic receptors seems to contribute to motor dysfunction in advanced Parkinson's disease (PD). With severe dopaminergic denervation, exogenous levodopa is largely decarboxylated to dopamine in serotonergic terminals. If 5-HT1A autoreceptors regulate dopamine as well as serotonin release, in parkinsonian patients inhibition of striatal serotonergic neuron firing might help maintain more physiological intrasynaptic dopamine concentrations and thus ameliorate motor fluctuations and dyskinesias. To evaluate this hypothesis, effects of a selective 5-HT1A agonist, sarizotan, given orally at 2 and 5 mg twice daily to 18 relatively advanced parkinsonian patients, were compared with baseline placebo function during a 3-week, double-blind, placebo-controlled, proof-of-concept study. Sarizotan alone or with intravenous levodopa had no effect on parkinsonian severity. But at safe and tolerable doses, sarizotan coadministration reduced levodopa-induced dyskinesias and prolonged its antiparkinsonian response (P < or = 0.05). Under the conditions of this study, our findings suggest that 5-HT1A receptor stimulation in levodopa-treated parkinsonian patients can modulate striatal dopaminergic function and that 5-HT1A agonists may be useful as levodopa adjuvants in the treatment of PD.

Improving the translation of novel findings from basic laboratory research to better therapies for neurologic disease constitutes a major challenge for the neurosciences. This brief review of aspects of the development of an adenosine A2A antagonist for use in the management of Parkinson's disease (PD) illustrates approaches to some of the relevant issues. Adenosine A2A receptors, highly expressed on striatal medium spiny neurons, signal via kinases whose aberrant activation has been linked to the appearance of parkinsonian signs after dopaminergic denervation and to the motor response complications produced by dopaminomimetic therapy. To assess the ability of A2A receptor blockade to normalize certain of these kinases and thus benefit motor dysfunction, the palliative and prophylactic effects of the selective antagonist KW6002 were first evaluated in rodent and primate models. In hemiparkinsonian rats, KW6002 reversed the intermittent L-dopa treatment-induced, protein kinase A-mediated hyperphosphorylation of striatal alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptor GluR1 S845 residues and the concomitant shortening in motor response duration. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys, coadministration of KW6002 with daily apomorphine injections acted prophylactically to prevent dyskinesia onset. These and related preclinical observations guided the design of a limited, randomized, controlled, proof-of-concept study of the A2A antagonist in patients with moderately advanced PD. Although KW6002 alone or in combination with a steady-state IV infusion of optimal-dose L-dopa had no effect on parkinsonian severity, the drug potentiated the antiparkinsonian response to low-dose L-dopa with fewer dyskinesias than produced by optimal-dose L-dopa alone. KW6002 also safely prolonged the efficacy half-time of L-dopa. The results suggest that drugs capable of selectively blocking adenosine A2A receptors could confer therapeutic benefit to L-dopa-treated parkinsonian patients and warrant further evaluation in phase II studies. They also illustrate a strategy for successfully bridging a novel approach to PD therapy from an evolving research concept to pivotal clinical trials.

Dopamine reuptake blockers, by enhancing and stabilizing intrasynaptic transmitter levels, could help palliate motor dysfunction in Parkinson's disease. This randomized, double-blind, placebo-controlled study compared the acute effects of the monoamine uptake inhibitor NS 2330 to those of placebo in 9 relatively advanced parkinsonian patients. At the dose administered, no change in parkinsonian scores was found when NS 2330 was given alone or with levodopa. Moreover, NS 2330 coadministration did not appear to alter dyskinesia severity or the duration of the antiparkinsonian response to levodopa. The drug was well tolerated. Under the conditions of this study, the present results failed to support the usefulness of dopamine reuptake inhibition in the treatment of advanced Parkinson's disease.