Effects of a selective partil D₁ agonist, CY 208‐243, in de novo patients with Parkinson disease

Abstract

A selective dopamine D1-receptor agonist, CY 208-243, was administered to 23 de novo patients who had had Parkinson disease (PD) for less than or equal to 3 months. The drug was first used as monotherapy and then in some patients in combination with a dopamine D2-receptor agonist, bromocriptine. Results showed that CY 208-243 exerted a mild antiparkinsonian action, and tremor was the main symptom that consistently improved. The addition of bromocriptine less than or equal to 15 mg to CY 208-243 did not result in additional improvement, but this might be due to the short duration of treatment and the low doses of bromocriptine. The study was prematurely discontinued for safety reasons. We conclude that D1-receptor stimulation may result in improvement of motor disability in PD.

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…Thus, de novo treatment with the D 1 agonist SKF-81,297 led to the development of AIMs in the 6-OHDA-lesioned rat (Dupre et al, 2007;Jaunarajs et al, 2009), and de novo administration of the D 1 agonist SFK-82,958 led to the development of dyskinesia in the MPTP-lesioned macaque (Blanchet et al, 1996b;Goulet et al, 1996). To our knowledge, only one de novo study with a selective D 1 agonist was performed in PD patients; in that study, no dyskinesia was reported after treatment with the D 1 partial agonist CY-208,243 (Emre et al, 1992). D 2 receptors also appear to be involved in dyskinesia, although they are traditionally regarded as being less involved than D 1 receptors, perhaps because of the de novo studies with dopamine agonists and of the postmortem data discussed above.…”

Dopamine D1 receptor ligands: Where are we now and where are we going

“…Several compounds, with high binding affinity and selectivity for the D 1 receptor had even entered clinical trials as anti-parkinsonian or anti-psychotic drugs, but were discontinued later or no development information reported for several years. [134][135][136][137] These ligands include conformationally flexible benzazepines, for example, SKF-83566 (2) In addition to their low intrinsic partial agonist activity, the failure of these compounds was largely due to poor oral bioavailability and rapid tolerance.…”

Striatal and nigral D 1 mechanisms involved in the antiparkinsonian effects of SKF 82958 (APB): studies of tremulous jaw movements in rats

“…Recent evidence indicates that tacrine-induced jaw movements are reduced by SKF 82958 but not by SKF 38393 ), a pattern which is similar to the effects of these agents in MPTP parkinsonism. Interest in D 1 agonists as potential antitremorogenic agents is warranted, in view of a clinical report indicating that the D 1 agonist CY 208-243 suppressed parkinsonian tremor; according to Emre et al (1992), CY 208-243 exerted a mild antiparkinsonian effect, but "tremor was the main symptom that consistently improved" (p. 239).…”