Receptor signaling and behavioral properties of EFF0311, a longer‐acting selective full D1 agonist as a potential treatment for Parkinson's disease

D 1 dopamine full agonists like dihydrexidine (DHX) were previously used to show that D 1 , but not D 2 , agonists could match the efficacy of levodopa in the primate MPTP Parkinson's disease (PD) model and in humans with PD. Short duration of action, toxicity, and/or limited bioavailability have prevented a D 1 agonist from being approved for clinical use, with only DHX (very short acting) available for limited investigator‐initiated clinical studies. We now report the properties of EFF0311, a DHX analog with greater D 1 selectivity and nanomolar affinity for D 1 and D 5 receptors. EFF0311 had 100% intrinsic activity in stimulating adenylate cyclase via D 1 receptors in expressed systems or brain. EFF0311 (relative to quinpirole) was far less potent at D 2L ‐mediated stimulation of arachidonic acid release than in inhibition of forskolin‐stimulated adenylate cyclase, consistent with functionally selective actions at D 2L receptors. In the unilateral 6‐OHDA rat model of PD, EFF0311 effects lasted 3–5 times longer than DHX. These behavioral effects were completely blocked by a D 1 antagonist, but not decreased by a D 2 antagonist. The properties of EFF0311 (D 1 full agonism, longer duration of action, atypical D 2 actions) suggest it may be an ideal PD drug candidate. Grant support: MH082441, MH040537, PA Keystone Innovation Grant (RBM), NS042402 and PA Tobacco settlement fund (TS). RBM has a potential CoI.